This invention relates to new propanolamine derivatives which is the xcex23 adrenergic receptor agonist and salts thereof which are useful as a medicament.
This invention relates to new propanolamine derivatives which is the xcex23 adrenergic receptor agonist and salts thereof.
More particularly, it relates to new propanolamine derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, overflow incontinence, passive incontinence, reflux incontinence, urge incontinence, urinary stress incontinence or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression and the like.
One object of this invention is to provide new and useful propanolamine derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence and anti-pollakiuria activities.
Another object of this invention is to provide processes for the preparation of said propanolamine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said propanolamine derivatives and salts thereof.
Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said propanolamine derivatives and salts thereof.
The object propanolamine derivatives of this invention are new and can be represented by the following general formula [I]: 
wherein
R1 is aryl which may have one or more suitable substituent(s), heterocyclic group or cyclo(lower)alkyl,
R2 is hydrogen or amino protective group,
R3 and R4 are independently hydrogen, halogen, hydroxy, amino, nitro, carboxy, protected carboxy, aryl, lower alkyl, hydroxy(lower)alkyl, amino(lower)alkyl, acyloxy(lower)alkyl, acylamino(lower)alkyl, lower alkylamino(lower)alkyl which may have one or more suitable substituent(s), mono or di-(lower)alkylamino, acylamino, acyl group, lower alkoxy, halo(lower)alkoxy, lower alkenyloxy, lower alkoxy(lower)alkoxy, aryloxy, cyclo(lower)alkyloxy, heterocyclicoxy, ar(lower)alkyloxy, acyloxy or acyl(lower)alkoxy,
R5 is hydrogen, lower alkyl, or aryl,
A is lower alkylene which may have one or more suitable substituent(s) or lower alkenylene,
X is O, S, SO, SO2 or NH, and
m is an integer of 0 or 1.
The object compound [I] or a salt thereof can be prepared by the following processes. 
wherein
R1, R2, R3, R4, R5, A, X and m are each as defined above, and
Ra2 is amino protective group.
In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
The preferable number of the xe2x80x9cone or morexe2x80x9d in the term of xe2x80x9cone or more suitable substituent(s)xe2x80x9d may be 1 to 4.
Suitable example of xe2x80x9chalogenxe2x80x9d may be fluoro, chloro, bromo, iodo, and the like.
Suitable example of xe2x80x9clower alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.
Suitable example of xe2x80x9chigher alkylxe2x80x9d may include straight or branched one having 7 to 20 carbon atoms, such as heptyl, octyl, 3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, and the like.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d moiety may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, 1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like.
Suitable example of xe2x80x9carylxe2x80x9d and xe2x80x9carxe2x80x9d moiety may include phenyl which may have lower alkyl (e.g., phenyl, mesityl, tolyl, etc.), naphthyl, anthryl, and the like, in which the preferred one may be phenyl and naphthyl.
Suitable example of xe2x80x9caroylxe2x80x9d moiety may include benzoyl, toluoyl, naphthoyl, anthrylcarbonyl, and the like, in which the preferred one may be benzoyl and naphthoyl.
Suitable example of xe2x80x9cprotected carboxyxe2x80x9d may be a conventional protecting group such as an esterified carboxy group, or the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.] which may have suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester [e.g. 2-mesylethyl ester, etc.] or mono(or di or tri)halo(lower)alkyl ester [e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.];
higher alkyl ester [e.g. heptyl ester, octyl ester, 3,5-dimethyloctyl ester, 3,7-dimethyloctyl ester, nonyl ester, decyl ester, undecyl ester, dodecyl ester, tridecyl ester, tetradecyl ester, pentadecyl ester, hexadecyl ester, heptadecyl ester, octadecyl ester, nonadecyl ester, adamantyl ester, etc.];
lower alkenyl ester [e.g. (C2-C6)alkenyl ester (e.g. vinyl ester, allyl ester, etc.)];
lower alkynyl ester [e.g. (C2-C6)alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.)];
ar(lower)alkyl ester which may have one or more suitable substituent(s) [e.g. phenyl(lower)alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo(lower)alkyl (e.g. benzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)];
aryl ester which may have one or more suitable substituent(s) [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.)];
cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1-(or 2-)[cyclopentyloxycarbonyloxy]ethyl ester, 1-(or 2-)[cyclohexyloxycarbonyloxy]ethyl ester, 1-(or 2-)-[cycloheptyloxycarbonyloxy]ethyl ester, etc.), etc.];
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)methyl ester, 1-(or 2-)(5-methyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-ethyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, 1-(or 2-)(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; or the like,
in which the preferred one may be lower alkyl ester, lower alkanoyloxy(lower)alkyl ester, ar(lower)alkyl ester which may have one or more suitable substituent(s), cycloalkyloxycarbonyloxy(lower)alkyl ester which may have lower alkyl, higher alkyl ester, and [5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl](lower)alkyl ester;
and the more preferred one may be methyl ester, ethyl ester, isobutyl ester, butyl ester, pentyl ester, hexyl ester, benzyl ester, 4-trifluoromethylbenzyl ester, 4-chlorobenzyl ester, adamantyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (1-cyclohexyloxycarbonyloxy)ethyl ester and pivaloyloxymethyl ester, and the like, in which the preferred one may be (C1-C4)alkyl ester, and the most preferred one may be ethyl ester.
Suitable xe2x80x9cacyl groupxe2x80x9d and xe2x80x9cacylxe2x80x9d moiety may include carbamoyl, sulfamoyl, sulfinamoyl, sulfenamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows :
carbamoyl; sulfamoyl; sulfinamoyl; sulfenamoyl; aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.); protected carboxy such as commonly protected carboxy [e.g., esterified carboxy such as lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.], or the like; lower alkylcarbamoyl (e.g., methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc.);
lower or higher alkylsulfonyl (e.g., methylsulfonyl, dimethylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.);
di-(lower)alkoxyphosphoryl (e.g, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.), lower alkylsulfamoyl (e.g., methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, propylsulfamoyl, butylsulfamoyl, pentylsulfamoyl hexylsulfamoyl, etc.),
aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];
ar(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.);
aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxcarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.);
arylcarbamoyl (e.g., phenylcarbamoyl, etc.);
arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.); arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like.
heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexanoyl, etc.); heterocyclicglyoxyloyl;
or the like; and the like.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d moiety may include
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, dihydroindolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom, for example, tetrahydrofuran, tetrahydropyran, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like, and the abovementioned xe2x80x9cheterocyclic groupxe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d moiety may have one or more suitable substituent(s) such as amino, oxo, cyano, aryl, ar(lower)alkyl, heterocyclc group.
Suitable example of xe2x80x9ccyclo(lower)alkylxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which the preferred one may be cyclo(C4-C6)alkyl, and the most preferred one may be cyclopentyl and cyclohexyl.
Suitable example of xe2x80x9camino protective groupxe2x80x9d moiety may be common amino protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one may be lower alkoxycarbonyl and phenyl(lower)alkyl, and the most preferred one may be tert-butoxycarbonyl and benzyl.
Suitable example of xe2x80x9carylxe2x80x9d moiety in the term of xe2x80x9caryl which may have one or more suitable substituent(s)xe2x80x9d in R1 can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9caryl which may have one or more suitable substituent(s)xe2x80x9d may include hydroxy, halogen, lower alkylsulfonylamino, lower alkanoylamino, and the like.
Suitable example of xe2x80x9clower alkylsulfonylaminoxe2x80x9d may include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, and the like, in which the preferred one may be (C1-C4)alkylsulfonylamino, and the most preferred one may be methylsulfonylamino.
Suitable example of xe2x80x9clower alkanoylaminoxe2x80x9d may include formylamino, acetylamino, propanoylamino, butanoylamino, 2-methylpropanoylamino, pentanoylamino, hexanoylamino, and the like, in which the preferred one may be (C1-C4)-alkanoylamino, and the most preferred one may be acetylamino.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d in R1 can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) which may have one or more suitable substituent(s), and unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) which may have one or more suitable substituent(s), and the most preferred one may be pyridyl, aminopyridyl, indolyl and benzimidazolone.
Suitable example of xe2x80x9ccyclo(lower)alkylxe2x80x9d in R1 can be referred to aforementioned xe2x80x9ccyclo(lower)alkylxe2x80x9d, in which the preferred one may be cyclo(C4-C6)alkyl, and the most preferred one may be cyclopentyl.
Suitable example of xe2x80x9cmono or di lower alkylaminoxe2x80x9d may include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, methylbutylamino, sec-butylamino, 1-methylpentylamino, ethylpentylamino, hexylamino, and the like, in which the preferred one may be mono or di(C1-4)alkylamino, and the most preferred one may be dimethylamino.
Suitable example of xe2x80x9chydroxy(lower)alkylxe2x80x9d may include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like, in which the preferred one may be hydroxy(C1-C4)alkyl, and the most preferred one may be hydroxymethyl.
Suitable example of xe2x80x9camino(lower)alkylxe2x80x9d may include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, aminohexyl, and the like, in which the preferred one may be amino(C1-C4)alkyl, and the most preferred one may be aminomethyl.
Suitable example of xe2x80x9cacylxe2x80x9d moiety in the term of xe2x80x9cacyloxy(lower)alkylxe2x80x9d can be referred to aforementioned xe2x80x9cacylxe2x80x9d, in which the preferred one may be lower alkanoyl, and the most preferred one may be acetyl.
Suitable example of xe2x80x9cacyloxy(lower)alkylxe2x80x9d may include lower alkanoyloxy(lower)alkyl, in which the preferred one may be (C1-C4)alkanoyloxy(C1-C4)alkyl, and the most preferred one may be acetyloxymethyl.
Suitable example of xe2x80x9cacylxe2x80x9d moiety in the term of xe2x80x9cacylamino(lower)alkylxe2x80x9d can be referred to aforementioned xe2x80x9cacylxe2x80x9d, in which the preferred one may be lower alkanoyl, aroyl, carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, and arylsulfonyl.
Suitable example of xe2x80x9cacylamino(lower)alkylxe2x80x9d may include lower alkanoylamino(lower)alkyl, aroylamino(lower)alkyl, carbamoylamino(lower)alkyl, lower alkylcarbamoylamino(lower)alkyl, lower alkylsulfonylamino(lower)alkyl, arylsulfonylamino(lower)alkyl and the like, in which the preferred one may be (C1-C4)alkanoylamino(C1-C4)alkyl, benzoylamino(C1-C4)alkyl, carbamoylamino(C1-C4)alkyl, (C1-C4)alkylsulfonylamino(C1-C4)alkyl and phenylsulfonylamino(C1-C4)alkyl, and the most referred one may be acetylaminomethyl, benzoylaminomethyl, carbamoylaminomethyl, butylcarbamoylaminomethyl, methylsulfonylaminomethyl and phenylsulfonylaminomethyl.
Suitable example of xe2x80x9csuitable substituentxe2x80x9d moiety in the term of xe2x80x9clower alkylamino(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may include lower alkyl and carboxy, in which the preferred one may be methyl and carboxy.
Suitable example of xe2x80x9clower alkylamino(lower)alkyl which may have one or more suitable substituent(s)xe2x80x9d may include di(lower)alkylamino(lower)alkyl, carboxy(lower)alkylamino(lower)alkyl, and the like, in which the preferred one may be di(C1-C4)alkylamino(C1-C4)alkyl and carboxy(C1-C4)-alkylamino(C1-C4)alkyl, and the most preferred one may be dimethylaminomethyl and carboxyethylaminomethyl.
Suitable example of xe2x80x9cacylxe2x80x9d moiety in the term of xe2x80x9cacylaminoxe2x80x9d can be referred to aforementioned xe2x80x9cacylxe2x80x9d moiety, in which the preferred one may be lower alkanoyl, aroyl, lower alkoxycarbonyl, aryloxycarbonyl, lower alkylsulfonyl, phenylsulfonyl, sulfamoyl, lower alkylsulfamoyl, and the most preferred one may be acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, methylsulfonyl, phenylsulfonyl, sulfamoyl and dimethylsulfamoyl.
Suitable example of xe2x80x9cacylaminoxe2x80x9d may be acetylamino, benzoylamino, methoxycarbonylamino, phenoxycarbonylamino, methylsulfonylamino, phenylsulfonylamino, sulfamoylamino and dimethylsulfamoylamino.
Suitable example of xe2x80x9cacyl groupxe2x80x9d can be referred to aforementioned xe2x80x9cacyl groupxe2x80x9d, in which the preferred one may be carbamoyl, lower alkylcarbamoyl, arylcarbamoyl, and the most preferred one may be carbamoy, methylcarbamoyl, dimethylcarbamoyl and phenylcarbamoyl.
Suitable example of xe2x80x9clower. alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9clower alkoxyxe2x80x9d, in which the preferred one may be methoxy, ethoxy, propoxy, isopropoxy and benzyloxy.
Suitable example of xe2x80x9chalo(lower)alkoxyxe2x80x9d may be fluoro(lower)alkoxy, chloro(lower)alkoxy, bromo(lower)alkoxy, iodo(lower)alkoxy, and the like, in which the preferred one may be fluoro(C1-C4)alkoxy, chloro(C1-C4)alkoxy, bromo(C1-C4)alkoxy, iodo(C1-C4)alkoxy, and the most preferred one may be fluoromethoxy.
Suitable example of xe2x80x9clower alkenyloxyxe2x80x9d may include vinyloxy, 1-(or 2-)propenyloxy, 1-(or 2- or 3-)butenyloxy, 1-(or 2- or 3- or 4-)pentenyloxy, 1-(or 2- or 3- or 4- or 5-)hexenyloxy, and the like, in which the preferred one may be (C2-C4)alkenyloxy, and the most preferred one may be 2-propenyloxy.
Suitable example of xe2x80x9clower alkoxy(lower)alkoxyxe2x80x9d may include methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxypropoxy, ethoxyethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, hexyloxyethoxy, and the like, in which the preferred one may be (C1-C4)alkoxy-(C1-C4)alkoxy, and the most preferred one may be methoxyethoxy.
Suitable example of xe2x80x9caryloxyxe2x80x9d may include phenoxy, mesityloxy, tolyloxy, naphthyloxy, anthryloxy, and the like, in which the preferred one may be phenoxy.
Suitable example of xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d may include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like, in which the preferred one may be cyclopentyloxy.
Suitable example of xe2x80x9cheterocyclicxe2x80x9d moiety in the term of xe2x80x9cheterocyclicoxyxe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclicxe2x80x9d moiety, in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms(s) which may have a suitable substituent, and the most preferred one may be pyridyl having cyano.
Suitable example of xe2x80x9cheterocyclicoxyxe2x80x9d may be pyridyloxy having cyano.
Suitable example of xe2x80x9car(lower)alkyloxyxe2x80x9d may include phenyl(lower)alkyloxy, mesityl(lower)alkyloxy, tolyl(lower)alkyloxy, naphthyl(lower)alkyloxy, anthryl(lower)alkyloxy, and the like, in which the preferred one may be phenyl(C1-C4)alkyloxy, and the most preferred one may be benzyloxy and phenetyloxy.
Suitable example of xe2x80x9cacylxe2x80x9d moiety in the term of xe2x80x9cacyloxyxe2x80x9d can be referred to aforementioned xe2x80x9cacylxe2x80x9d moiety, in which the preferred one may be carbamoyl and mono or di-lower alkylsulfamoyl, and the most preferred one may be carbamoyl and dimethylsulfamoyl.
Suitable example of xe2x80x9cacyloxyxe2x80x9d may be carbamoyloxy and mono or di lower alkylsulfamoyloxy and the most preferred one may be carbamoyloxy and dimethylsulfamoyloxy.
Suitable example of xe2x80x9clower alkoxyxe2x80x9d moiety in the term of xe2x80x9cacyl(lower)alkoxyxe2x80x9d can be referred to aforementioned xe2x80x9clower alkoxyxe2x80x9d, in which the preferred one may be (C1-C4)alkoxy, and the most preferred one may be methoxy.
Suitable example of xe2x80x9cacylxe2x80x9d moiety in the term of xe2x80x9cacyl(lower)alkoxyxe2x80x9d may include the aforementioned xe2x80x9cacylxe2x80x9d moiety; lower alkylcarbamoyl which may have one or more suitable substituent(s) selected from the group consisting of hydroxy, lower alkoxy, lower alkyl, ar(lower)alkyl, protected carboxy, carboxy, mono or di lower alkylamino, lower alkylthio, halo(lower)alkyl, aryl which may have one or more suitable substituent(s), and heterocyclic group; arylcarbamoyl which may have one or more suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, halogen, halo(lower)alkyl, mono or di-lower alkylamino, lower alkoxy, halo(lower)alkoxy and nitro; heterocycliccarbamoyl which may have one or more suitable substituent(s) selected from the group consisting of ar(lower)alkyl, aryl and heterocyclic(lower)alkyl which may be substituted with heterocyclic group; heterocycliccarbonyl which may have one or more suitable substituent(s) selected from the group consisting of ar(lower)alkyl and heterocyclic group which may be substituted with one or more suitable substituent(s); cyclo(lower)alkylcarbamoyl;guanidinocarbonyl; and the like.
Suitable example of xe2x80x9clower alkylcarbamoylxe2x80x9d may include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, 1-methylbutylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, tert-pentylcarbamoyl, 1-methylpentylcarbamoyl, neopentylcarbamoyl, hexylcarbamoyl, isohexylcarbamoyl, and the like, in which the preferred one may be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl, isobutylcarbamoyl, 1-methylbutylcarbamoyl, and hexylcarbamoyl.
Suitable example of xe2x80x9clower alkoxyxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkoxyxe2x80x9d, in which the preferred one may be (C1-C4)alkoxy, and the most preferred one may be methoxy, ethoxy and propoxy.
Suitable example of xe2x80x9clower alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may nave one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkylxe2x80x9d, in which the preferred one may be (C1-C4)alkyl, and the most preferred one may be methyl and ethyl.
Suitable example of xe2x80x9car(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include xe2x80x9cmono- or di- or tri-phenyl(lower)alkylxe2x80x9d such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl, and the like, in which the preferred one may be benzyl.
Suitable example of xe2x80x9cprotected carboxyxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cprotected carboxyxe2x80x9d, in which the preferred one may be (C1-C4)alkyl ester, and the most preferred one may be ethyl ester.
Suitable example of xe2x80x9cmono or di-lower alkylaminoxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, tert-pentylamino, 1-methylpentylamino, neopentylamino, hexylamino, isohexylamino, and the like, in which the preferred one may be di(C1-C4)alkylamino, and the most preferred one may be dimethylamino and diethylamino.
Suitable example of xe2x80x9clower alkylthioxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include methylthio, ethylthio, propylthio, butylthio, pentylthio, and the like, in which the preferred one may be (C1-C4)alkylthio, and the most preferred one may be methylthio.
Suitable example of xe2x80x9chalo(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9clower alkylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include tri-halo(lower)alkyl such as trichloromethyl, trichloroethyl, trichloropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, tribromomethyl, tribromoethyl, and the like, in which the preferred one may be tri-halo(C1-C4)alkyl, and the most preferred one may be trifluoromethyl and trifluoroethyl.
Suitable example of xe2x80x9carylxe2x80x9d in the term of xe2x80x9caryl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d in the term of xe2x80x9caryl which may have one or more suitable substituent(s)xe2x80x9d may include mono or di(lower)alkylamino(lower)alkyl (e.g., methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, propylaminopropyl, butylaminoethyl, diethylaminopentyl, etc.), in which the preferred one may be mono or di(C1-C4)alkylamino(C1-C4)alkyl, and the most preferred one may be dimethylaminomethyl.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be saturated or unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) and saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), and the most preferred one may be pyridyl, imidazolyl and morpholino.
Suitable example of xe2x80x9carylxe2x80x9d moiety in the term of xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9clower alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkylxe2x80x9d, in which the preferred one may be (C1-C4)alkyl, and the most preferred one may be methyl and butyl.
Suitable example of xe2x80x9chigher alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9chigher alkylxe2x80x9d, in which the preferred one may be (C7-C10)alkyl, and the most preferred one may be octyl.
Suitable example of xe2x80x9chalo(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include tri-halo(lower)alkyl such as trichloromethyl, trichloroethyl, trichloropropyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, tribromomethyl, tribromoethyl, and the like, in which the preferred one may be tri-halo(C1-C4)alkyl, and the most preferred one may be trifluoromethyl.
Suitable example of xe2x80x9cmono or di-lower alkylaminoxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, tert-pentylamino, 1-methylpentylamino, neopentylamino, hexylamino, isohexylamino, and the like, in which the preferred one may be di(C1-C4)alkylamino, and the most preferred one may be dimethylamino.
Suitable example of xe2x80x9clower alkoxyxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkoxyxe2x80x9d, in which the preferred one may be (C1-C4)alkoxy, and the most preferred one may be methoxy.
Suitable example of xe2x80x9chalo(lower)alkoxyxe2x80x9d in the suitable substituent(s) of the term xe2x80x9carylcarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include fluoromethoxy, fluoroethoxy, trifluoromethoxy, chloromethoxy, chloroethoxy, trichloroethoxy, bromomethoxy, iodoethoxy, and the like, in which the preferred one may be halo(C1-C4)alkoxy, and the most preferred one may be fluoromethoxy.
Suitable example of xe2x80x9cheterocyclicxe2x80x9d moiety in the term of xe2x80x9cheterocyclicarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclicxe2x80x9d moiety, in which the preferred one may be saturated or unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) and unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), and the most preferred one may be piperidyl, tetrazolyl, indolyl and thiazolyl.
Suitable example of xe2x80x9car(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbamoyl which may have one or more suitable substituent(s)xe2x80x9d may include xe2x80x9cmono- or di- or tri-phenyl(lower)alkylxe2x80x9d such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl, and the like, in which the preferred one may be benzyl.
Suitable example of xe2x80x9clower alkylxe2x80x9d moiety in the term of xe2x80x9cheterocyclic(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9clower alkylxe2x80x9d, in which the preferred one may be (C1-C4)alkyl, and the most preferred one may be methyl.
Suitable example of xe2x80x9cheterocyclicxe2x80x9d moiety in the term of xe2x80x9cheterocyclic(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclicxe2x80x9d, in which the preferred one may be saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be piperidyl.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d in the term of xe2x80x9cheterocyclic(lower)alkyl which may be substituted with heterocyclic groupxe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbamoyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be indolyl.
Suitable example of xe2x80x9cheterocyclicxe2x80x9d moiety in the term of xe2x80x9cheterocycliccarbonyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclicxe2x80x9d moiety, in which the preferred one may be saturated 3 to 8-membered heteromonocyclic group containing to 4 nitrogen atom(s) and unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be piperidyl, piperazinyl and dihydroindolyl.
Suitable example of xe2x80x9car(lower)alkylxe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbonyl which may have one or more suitable substituent(s)xe2x80x9d may include xe2x80x9cmono- or di- or tri-phenyl(lower)alkylxe2x80x9d such as benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, benzhydryl, trityl, and the like, in which the preferred one may be benzhydryl.
Suitable example of xe2x80x9cheterocyclic groupxe2x80x9d moiety in the term xe2x80x9cheterocyclic group which may have one or more suitable substituent(s)xe2x80x9d in the suitable substituent(s) of the term xe2x80x9cheterocycliccarbonyl which may have one or more suitable substituent(s)xe2x80x9d can be referred to aforementioned xe2x80x9cheterocyclic groupxe2x80x9d, in which the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), and the most preferred one may be pyridazinyl.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d in the term of xe2x80x9cheterocyclic group which may be substituted with one or more suitable substituent(s)xe2x80x9d may include oxo and aryl, in which the preferred one may be oxo and phenyl.
Suitable example of xe2x80x9ccyclo(lower)alkylcarbamoylxe2x80x9d may include cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, and the like, in which the preferred one may be cyclo(C4-C6)alkylcarbamoyl, and the most preferred one may be cyclohexylcarbamoyl.
Suitable example of xe2x80x9clower alkylxe2x80x9d in R5 can be referred to aforementioned xe2x80x9clower alkylxe2x80x9d, in which the preferred one may be (C1-C4)alkyl, and the most preferred one may be methyl.
Suitable example of xe2x80x9cacyl(lower)alkoxyxe2x80x9d may include carbamoyl(lower)alkoxy, lower alkylcarbamoyl(lower)alkoxy, cyclo(lower)alkylcarbamoyl(lower)alkoxy, arylcarbamoyl(lower)alkoxy, heterocyclicccarbamoyl(lower)alkoxy, N-lower alkyl-lower alkylcarbamoyl(lower)alkoxy, ar(lower)alkylcarbamoyl(lower)alkoxy, lower alkoxy(lower)alkylcarbamoyl(lower)alkoxy, lower alkylthio(lower)alkylcarbamoyl(lower)alkoxy, di(lower)alkylamino(lower)alkylcarbamoyl(lower)alkoxy, heterocycliccarbonyl(lower)alkoxy, guanidinocarbonyl(lower)alkoxy, hydroxy(lower)alkylcarbamoyl(lower)alkoxy, halo(lower)alkylcarbamoyl(lower)alkoxy, protected carboxy(lower)alkylcarbamoyl(lower)alkoxy having protected carboxy, heterocyclic(lower)alkylcarbamoyl(lower)alkoxy, heterocycliccarbamoyl(lower)alkoxy having aryl(lower)alkyl, arylcarbamoyl(lower)alkoxy having higher alkyl, arylcarbamoyl(lower)alkoxy having lower alkyl, arylcarbamoyl(lower)alkoxy having halo(lower)alkyl, arylcarbamoyl(lower)alkoxy having nitro, arylcarbamoyl(lower)alkoxy having halogen, arylcarbamoyl(lower)alkoxy having di(lower)alkylamino(lower)alkyl, heterocycliccarbonyl(lower)alkoxy having benzhydryl, lower alkylcarbamoyl(lower)alkoxy having benzhydryl, heterocycliccarbamoyl(lower)alkoxy having heterocyclic(lower)alkyl substituted with heterocyclic group, heterocycliccarbonyl(lower)alkoxy having heterocyclic group substituted with oxo and aryl, N-lower alkyl-ar(lower)alkylcarbamoyl(lower)alkoxy, N-ar(lower)alkyl-ar(lower)alkylcarbamoyl(lower)alkoxy, N-lower alkyl-heterocyclic(lower)alkylcarbamoyl(lower)alkoxy, arylcarbamoly(lower)alkoxy having lower alkyl, arylcarbamoyl(lower)alkoxy having lower alkoxy, arylcarbamoyl(lower)alkoxy having halogen, arylcarbamoyl(lower)alkoxy having halo(lower)alkoxy, arylcarbamoyl(lower)alkoxy having di(lower)alkylamino, N-aryl-aryl(lower)alkylcarbamoyl(lower)alkoxy, N-lower alkyl-cyclo(lower)alkylcarbamoyl(lower)alkoxy,
in which the preferred one may be carbamoyl(C1-C4)-alkoxy, (C1-C6)alkylcarbamoyl(C1-C4)alkoxy, cyclo(C4-C6)-alkylcarbamoyl(C1-C4)alkoxy, phenylcarbamoyl(C1-C4)alkoxy, carbamoyl(C1-C4)alkoxy substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoyl(C1-C4)alkoxy substituted with unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), N-(C1-C4)alkyl-(C1-C6)alkylcarbamoyl(C1-C4)alkoxy, phenyl(C1-C4)alkylcarbamoyl (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, (C1-C4)alkylthio(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, carbonyl(lower)alkoxy substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), guanidinocarbamoyl(C1-C4)alkoxy, hydroxy(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, tri-halo(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, esterified carboxy(C1-C4)alkylcarbamoyl(C1-C4)alkoxy having esterified carboxy, (C1-C4)alkylcarbamoyl(C1-C4)alkoxy substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), (C1-C4)alkylcarbamoyl(C1-C4)alkoxy substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoyl(C1-C4)alkoxy substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having aryl(lower)alkyl, phenylcarbamoyl(C1-C4)alkoxy having (C7-C14)alkyl, phenylcarbamoyl(C1-C4)alkoxy having (C1-C4)alkyl, phenylcarbamoyl(C1-C4)alkoxy having tri-halo(C1-C4)alkyl, phenylcarbamoyl(C1-C4)alkoxy having nitro, phenylcarbamoyl(C1-C4)alkoxy having halogen, phenylcarbamoyl(C1-C4)alkoxy having di(C1-C4)alkylamino-(C1-C4)alkyl, carbonyl(C1-C4)alkoxy substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having benzhydryl, (C1-C4)alkyl-carbamoyl(C1-C4)alkoxy having benzhydryl, carbamoyl(Cl-C4)-alkoxy substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) having (C1-C4)alkyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), carbonyl(C1-C4)alkoxy having unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) substituted with oxo and phenyl, N-(C1-C4)alkyl-phenyl-(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, N-phenyl(C1-C4)alkyl-phenyl(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, N-(C1-C4)alkyl-(C1-C4)alkylcarbamoyl(C1-C4)alkoxy having unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), N-(C1-C4)alkyl-(C1-C4)alkylcarbamoyl(C1-C4)alkoxy having unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), phenylcarbamoyl(C1-C4)alkoxy having (C1-C4)alkyl, phenylcarbamoyl(C1-C4)alkoxy having (C1-C4)alkoxy, phenylcarbamoyl(C1-C4)alkoxy having halogen, carbamoyl(C1-C4)alkoxy having unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), carbonyl(C1-C4)alkoxy substituted with unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), phenylcarbamoyl (C1-C4)alkoxy having di-halo(C1-C4)alkoxy, phenylcarbamoyl(C1-C4)alkoxy having di(C1-C4)alkylamino, N-phenyl-phenyl(C1-C4)alkylcarbamoyl(C1-C4)alkoxy, N-(C1-C4)alkyl-cyclo(C4-C6)alkylcarbamoyl(C1-C4)alkoxy,
and the most preferred one may be carbamoylmethoxy, ethylcarbamoylmethoxy, sec-butylcarbamoylmethoxy, n-butylcarbamoylmethoxy, hexylcarbamoylmethoxy, cyclohexylcarbamoylmethoxy, phenylcarbamoylmethoxy, tetrazolylcarbamoylmethoxy, indolylcarbamoylmethoxy, N-methyl-methylcarbamoylmethoxy, N-methyl-butylcarbamoylmethoxy, benzylcarbamoylmethoxy, methoxyethylcarbamoylmethoxy, methylthioethylcarbamoylmethoxy, dimethylaminoethylcarbamoylmethoxy, piperidinocarbonylmethoxy, guanidinocarbonylmethoxy, hydroxybutylcarbamoylmethoxy, 1-methylbutylcarbamoylmethoxy, 2-hydroxypropylcarbamoylmethoxy, ethoxypropylcarbamoylmethoxy, hydroxypropylcarbamoylmethoxy, diethylaminopropylcarbamoylmethoxy, tri-fluoroethylcarbamoylmethoxy, 1-ethoxycarbonyl-ethoxycarbonylmethylcarbamoylmethoxy, morpholinoethylcarbamoylmethoxy, pyridylethylcarbamoylmethoxy, pyridylmethylcarbamoylmethoxy, imidazolylpropylcarbamoylmethoxy, phenylbutylcarbamoylmethoxy, carbamoylmethoxy having piperidyl substituted with benzyl, octylphenylcarbamoylmethoxy, butylphenylcarbamoylmethoxy, tri-fluoromethylphenylcarbamoylmethoxy, nitrophenylcarbamoylmethoxy, fluorophenylcarbamoylmethoxy, dimethylaminomethylbenzylcarbamoylmethoxy, piperadinocarbonylmethoxy substituted with benzhydryl, benzhydrylmethylcarbamoylmethoxy, carbamoylmethoxy having thiazolyl having piperidinomethyl substituted with indolyl, piperidinocarbonylmethoxy having piridazinyl substituted with phenyl and oxo, N-methyl-benzylcarbamoylmethoxy, N-benzyl-benzylcarbamoylmethoxy, N-methoxy-indolylethylcarbamoylmethoxy, N-methyl-pyridylethylcarbamoylmethoxy, tolylcarbamoylmethoxy, methoxyphenylcarbamoylmethoxy, chlorophenylcarbamoylmethoxy, thiazolylcarbamoylmethoxy, dihydroindolylcarbonylmethoxy, di-fluoromethoxyphenylcarbamoylmethoxy, N-ethyl-propylcarbamoylmethoxy, N-methyl-methylpropylcarbamoylmethoxy, N-ethyl-butylcarbamoylmethoxy, N-methyl-hexylcarbamoylmethoxy, fluorophenylcarbamoylmethoxy, dimethylaminophenylcarbamoylmethoxy, N-phenyl-benzylcarbamoylmethoxy, N-methyl-phenethylcarbamoylmethoxy and N-methyl-cyclohexylcarbamoylmethoxy.
Suitable example of xe2x80x9clower alkylxe2x80x9d in R5 can be referred to aformentioned xe2x80x9clower alkylxe2x80x9d, in which the preferred one may be (C1-C4)alkyl, and the most preferred one may be methyl.
Suitable example of xe2x80x9carylxe2x80x9d in R5 can be referred to aforementioned xe2x80x9carylxe2x80x9d, in which the preferred one may be phenyl.
Suitable example of xe2x80x9clower alkylenexe2x80x9d moiety in the term of xe2x80x9clower alkylene which may have one or more suitable substituent(s)xe2x80x9d may include straight or branched one such as methylene, ethylene, trimethylene, 1-methylethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, 1-ethylethylene, 2-ethylpropylene, and the like, in which the preferred one may be (C1-C4)alkylene, and the most preferred one may be methylene, ethylene and 1-methylethylene.
Suitable example of xe2x80x9csuitable substituent(s)xe2x80x9d moiety in the term of xe2x80x9clower alkylene which may have one or more suitable substituent(s)xe2x80x9d may include aryl, in which the preferred one may be phenyl.
Suitable example of xe2x80x9clower alkenylenexe2x80x9d may include straight or branched one having 2 to 6 carbon atom(s) such as vinylene, propenylene, butenylene, 1 or 2 or 3-pentenylene, 1 or 2 or 3-hexenylene, methylvinylene, ethylvinylene, 1 or 2 or 3-methylpropenylene, 1 or 2 or 3-ethylpropenylene, 1 or 2 or 3 or 4-methyl-l or 2-butenylene, and the like, in which the preferred one may be (C2-C4)alkenylene, and the most preferred one may be vinylene.
The processes for preparing the object compound [I] are explained in detail in the following.
Process 1
The object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
Process 2
The object compound [Ib] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the amino protective group.
Suitable salts of the compounds [Ia] may be the same as those exemplified for the compound [I].
This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] and an acid addition salt compound [e.g. pyridine hydrochloride, etc.].
The elimination using trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like.
In case that the amino protective group is benzyl, the reduction is preferably carried out in the presence of a combination of palladium catalysts [e.g. palladium black, palladium on carbon, etc.] and formic acid or its salt [e.g. ammonium formate, etc.].
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], chlorobenzene, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
The object compound [I] or a salt thereof possesses gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystapathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, overflow incontinence, passive incontinence, reflux incontinence, urge incontinence, urinary incontinence, or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression, and the like.
The following compound to be used as the xcex23 adrenergic receptor agonist which is shown by formulas (IV), (V), (VI), (VII) and (VII) are also useful for the therapeutic treatment of dysuria, and the like. 
or a salt thereof, wherein
A is a bond, xe2x80x94(CH2)nxe2x80x94 or CH(B)xe2x80x94, where n is an integer of 1 to 3 and
B is xe2x80x94CN, xe2x80x94CON(R9)R9xe2x80x2or xe2x80x94CO2R7;
R1 is lower alkyl, aryl or arylalkyl;
R2 is hydrogen, hydroxy, alkoxy, xe2x80x94CH2OH, cyano, xe2x80x94C(O)OR7, xe2x80x94CO2H, xe2x80x94CONH2, tetrazole, xe2x80x94CH2NH2 or halogen;
R3 is hydrogen, alkyl, heterocycle or 
R4 is hydrogen, alkyl or B;
R5, R5xe2x80x2, R8, R8xe2x80x2 and R8xe2x80x3 are independently hydrogen, alkoxy, lower alkyl, halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94(CH2)nNR6COR7, CON(R6)R6xe2x80x2, xe2x80x94CON(R6)OR6xe2x80x3, xe2x80x94CO2R6, xe2x80x94SR7, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94N(R6)SO2R1, xe2x80x94N(R6)R6xe2x80x2, xe2x80x94NR6COR7, xe2x80x94OCH2CON(R6)R6xe2x80x2, xe2x80x94OCH2CO2R7 or aryl; or
R5 and R5xe2x80x2 or R8 and R8xe2x80x2 may together with the carbon atoms to which they are attached form an aryl or heterocycle;
R6 and R6xe2x80x2 are independently hydrogen or lower alkyl; and
R7 is lower alkyl;
R9 and R9xe2x80x2 are independently hydrogen, lower alkyl, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl; or
R9 and R9xe2x80x2 may together with the nitrogen atom to which they are attached form a heterocycle;
with the proviso that when
A is a bond or xe2x80x94(CH2)n and
R3 is hydrogen or unsubstituted alkyl,
xe2x80x83then
R4 is B or substituted alkyl: 
or a salt thereof, wherein
n is 0 to 5;
m is 0 or 1;
r is 0 to 3;
A is pyridinyl;
R1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) NR8R8, (6) SR8, (7) trifluoromethyl, (8) C1-C10 alkyl, (9) OR8, (10) SO2R9, (11) OCOR9, (12) NR8COR9, (13) COR9, (14) NR8SO2R9, (15) NR8CO2R8, or (16) C1-C10 alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR8, trifluoromethyl, OR8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, SO2R9, OCOR9, NR8SO2R9 or NR8CO2R8;
R2 and R3 are independently (1) hydrogen, (2) C1-C10 alkyl or (3) C1-C10 alkyl with 1 to 4 substituents selected from hydroxy, C1-C10 alkoxy, and halogen;
X is (1)xe2x80x94CH2xe2x80x94, (2) xe2x80x94CH2xe2x80x94CH2xe2x80x94, (3) xe2x80x94CHxe2x95x90CHxe2x80x94 or (4) xe2x80x94CH2Oxe2x80x94;
R4 and R5 are independently (1) hydrogen, (2) C1-C10 alkyl, (3) halogen, (4) NHR8, (5) OR8, (6) SO2R9 or (7) NHSO2R9;
R6 is (1) hydrogen or (2) C1-C10 alkyl;
R7 is Zxe2x80x94(R1a)n;
R1a is (1) R1, (2) C3-C8 cycloalkyl, (3) phenyl optionally substituted with up to 4 groups independently selected from R8, NR8R8, OR8, SR8 and halogen, or (4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, NR8R8, OR8, SR8, and halogen;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) a benzene ring fused to a C3-C8 cycloalkyl ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (6) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
R8 is (1) hydrogen, (2) C1-C10 alkyl, (3) C3-C8 cycloalkyl, (4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR10R10, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2-C1-C10 alkyl, SO2xe2x80x94C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, and Z optionally substituted by from 1 to 3 of halogen, C1-C10 alkyl or C1-C10 alkoxy, or (5) C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2xe2x80x94C1-C10 alkyl, SO2xe2x80x94C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, C1-C10 alkyl, and Z optionally substituted by from 1 to 4 of halogen, C1-C10 alkyl or C1-C10 alkoxy;
R9 is (1) R8 or (2) NR8R8; and
R10 is (1) C1-C10 alkyl, or (2) two R10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl: 
or a salt thereof, wherein
X is hydrogen, halogen, trifluoromethyl or lower alkyl, and
R is hydrogen; lower alkyl which may have a suitable substituent selected from the group consisting of cyclo(C3-C7)alkyl, hydroxy, lower alkoxy, carboxy and lower alkoxycarbonyl; cyclo(c3-C7) alkyl or lower alkanoyl: 
or a salt, ester or amide thereof, wherein
R1 is a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, hydroxymethyl, methyl, methoxyl, amino, formamido, acetamido, methylsulphonylamido, nitro, benzyloxy, methylsulphonylmethyl, ureido, trifluoromethyl or p-methoxybenzylamino group;
R2 is a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl group;
R3 is a hydrogen, chlorine or bromine atom or a hydroxyl group,
R4 is a hydrogen atom or a methyl group;
R5 is a hydrogen atom or a methyl group;
R6 is a hydrogen, fluorine or chlorine atom or a methyl, methoxyl or hydroxy group;
X is an oxygen atom or a bond;
Y is an alkylene group of up to 6 carbon atoms or a bond; and
Z is an alkylene, alkenylene or alkynylene group of up to 10 carbon atoms: or 
or a salt thereof, wherein
R is hydrogen or methyl,
R is hydrogen, halogen, hydroxy, benzyloxy, amino or hydroxymethyl,
R2 is hydrogen, hydroxymethyl, xe2x80x94NHR3, xe2x80x94SO2NR4R 4xe2x80x2 or nitro,
R3 is hydrogen, methyl, xe2x80x94SO2R5, formyl or xe2x80x94CONHR6xe2x80x2,
R4 and R4xe2x80x2 are independently hydrogen, lower alkyl or benzyl,
R5 is lower alkyl, benzyl or xe2x80x94NR4R4xe2x80x2,
R6 is hydrogen or lower alkyl,
R6xe2x80x2 is hydrogen or lower alkyl, and,
X is N, O, S or methylene;
when X is N, O or S,
then R9 is hydrogen,
either R7 or R8 is hydrogen, and
the other is hydrogen, amino, acetylamino or hydroxy;
when X is methylene,
then both R7 and R8 is hydrogen, and
R9 is hydrogen, amino, acetylamino or hydroxy.
The compounds (IV), (V), (VI), (VII) and (VIII) identified above or a salt thereof to be used in the present invention are the known ones and disclosed in EP-A2-659737, U.S. Pat. No. 5,561,142, EP-A1-211721, EP-A1-023385, and WO97/25311, respectively.
In the formula (IV), the terms xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d refers to both straight and branched chain groups having 1 to 12 carbon atoms, preferably 1 to 8 carbons. It is understood, therefore, that the terms xe2x80x9calkxe2x80x9d and xe2x80x9calkylxe2x80x9d denote both unsubstituted groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, n-hexyl and the like as well as substituted groups. The term xe2x80x9csubstituted alkylxe2x80x9d specifically denotes an alkyl group as defined above having one or more of the following substituents: halo (especially to form trihaloalkyl, particularly trichloromethyl or trifluoromethyl); aryl; cycloalkyl; hydroxy; amino; thiol; or Y, where Y is xe2x80x94CN, alkoxy, xe2x80x94CON(R6)R6xe2x80x2, xe2x80x94CO2R6 or xe2x80x94N(R6)SO2R1.
The term xe2x80x9clower alkylxe2x80x9d as employed herein includes such alkyl groups as described above containing 1 to 6 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d refers to any of the above alkyl groups linked to an oxygen atom.
The term xe2x80x9clower alkoxyxe2x80x9d refers to any of the above lower alkyl groups linked to an oxygen atom.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, or such groups optionally substituted with one or more substituents selected from hydrogen, alkoxy, lower alkyl, halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94(CH2)nNR6COR7, xe2x80x94CON(R6)R6xe2x80x2, xe2x80x94CON(R6)OR6xe2x80x2, xe2x80x94CO2R6, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94N(R6)SO2R1, xe2x80x94N(R6)R6xe2x80x2, xe2x80x94NR6COR7, xe2x80x94OCH2CON(R6)R6xe2x80x2, xe2x80x94OCH2CO2R7 or aryl. Phenyl and substituted phenyl are preferred.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, fluorine or iodine.
The term xe2x80x9cheterocyclexe2x80x9d refers to fully saturated or unsaturated rings of 5 or 6 atoms containing one or two oxygen and/or sulfur atoms and/or one to four nitrogen atoms provided that the total number of heteroatoms in the ring is four or less. Preferred monocyclic heterocycle groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl and imidazolyl. The term heterocycle also includes bicyclic rings wherein the five- or six-membered ring containing oxygen and/or sulfur and/or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available carbon atom. Preferred bicyclic heterocycle groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl, 4-, 5-, 6- or 7-benzofuranzanyl, 4-, 5-, 6- or 7-benzodioxolyl and 4-, 5-, 6- or 7-benzofuran. The term xe2x80x9cheterocyclexe2x80x9d also includes such monocyclic and bicyclic rings wherein an available carbon atom is substituted with one or more substituents selected from nitro, keto, azo, thiazo, hydrogen, alkoxy, lower alkyl, halogen, xe2x80x94OH, xe2x80x94CN, xe2x80x94(CH2)nNR6COR7, xe2x80x94CON(R6) R6xe2x80x2, xe2x80x94CON(R6)OR6xe2x80x2, xe2x80x94CO2R6, xe2x80x94SR7, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94N(R6)SO2R1, xe2x80x94N(R6)R6xe2x80x2, xe2x80x94NR6COR7, xe2x80x94OCH2CON(R6)R6xe2x80x2, xe2x80x94OCH2CO2R7 or aryl.
In the formula (V), the alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term xe2x80x9chalogenxe2x80x9d is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
Examples of 5 and 6-membered heterocycles and fused heterocycles of A, Z and R1a include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
The preferred values of A and Z are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
The more preferred values of A are phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
The more preferred values of Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl. When Z is attached to xe2x80x94NSO2(CH2)rxe2x80x94, it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. When Z is part of the definition of R8, it is preferably phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
The preferred heterocycles of R1a are thienyl, thiadiazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example. NR8R8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
In the formula (VI), the term xe2x80x9clower alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like.
The term xe2x80x9chalogenxe2x80x9d may include fluorine, chlorine, bromine, iodine, and the like.
The term xe2x80x9clower alkoxyxe2x80x9d may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, and the like.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d may include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, and the like.
The term xe2x80x9clower alkanoylxe2x80x9d may include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, and the like.
The term xe2x80x9ccyclo(C3-C7)alkylxe2x80x9d may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
In the formula (VII), the term xe2x80x9calkylenexe2x80x9d may include methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, tert-pentylene, neo-pentylene, hexylene, iso-hexylene, heptylene, octylene, nonylene, decylene, and the like.
The term xe2x80x9calkenylenexe2x80x9d may include vinylene, propenylene, butenylene, 1 or 2 or 3-pentenylene, 1 or 2 or 3-hexenylene, methylvinylene, ethylvinylene, heptenylene, octenylene, nonenylene, decenylene, and the like.
The term xe2x80x9calkynylenexe2x80x9d may include ethynylene, propynylene, butynylene, 1 or 2 or 3-pentynylene, 1 or 2 or 3-hexynylene, heptynylene, octynylene, nonynylene, decynylene, and the like.
In the formula (VIII), the term xe2x80x9clower alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like.
In order to show the usefulness of the compounds (IV) to (VIII) for the prophylactic and therapeutic treatment of above-mentioned diseases in a human being or an animal, the pharmacological test data of the representative compounds thereof are shown in the following.
Test 1
Effect on the increase in intravesical pressure induced by carbachol in anesthetized dog
Test Compound
(1) N-[5-[2-[1-(3,4-Dimethoxyphenyl)-2-phenylethylamino]-1(R)-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide (This compound was obtained according to a similar manner to that of Example 1 in EP-A2-659737.)
(2) N-[4-[2-[2(R)-Hydroxy-2-(pyridin-3-yl)ethylamino]ethyl]-phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]-benzenesulfonamide (This compound was obtained according to a similar manner to that of Example 70 in U.S. Pat. No. 5,561,142.)
(3) N-[5-[2-[2-(9H-Carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide hydrochloride (This compound was obtained according to a similar manner to that of Example 2 in WO97/25311.)
Test Method
Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and maintained under halothane anesthesia. A 12F Foley catheter was lubricated with water soluble jelly, inserted into the urethral orifice and advanced approximately 10 cm until the balloon tip was placed well inside the bladder. The balloon was then inflated with 5 ml of room air and catheter slowly withdrawn just part the first resistance that is felt at the bladder neck. Urine was completely drained out throught the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical pressure was continuously recorded. The test compound was injected intravenously at 5 minutes before the administration of carbachol (1.8 xcexcg/kg)
The test compounds (1), (2) and (3) inhibited the increase in intravesical pressure induced by carbachol.
Test 2
Effect on cystometrogram in anesthetized rat
Test Compound
(4-1-2(S)-[(7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-1(R)-(3-chlorophenyl)ethanol hydrochloride (This compound was obtained according to a similar manner to that of Example 11 in EP-A1-211721.)
Test Method
Male S.D. rats, aged 7-9 weeks, were anesthetized with urethane (1.2 g/kg, sc) and supine on a board. After a midline incision in the abdomen, the bladder was exposed. Polyethylene catheters, which were used to measure the intravesical pressure and to infuse saline, were inserted into the bladder through a small incision at the apex of the bladder dome. The bladder catheters were connected to an infusion pump and pressure transducer respectively. Saline was infused a rate of 5.0 ml/hr for 1 hour. Cystometrography was performed at 15 minutes intervals for 1 hour. The bladder capacity (volume) was calculated from the time required to fill the bladder. The test compound was administered intravenously via femoral vein.
The test compound (4) increased in bladder capacity at a dose of 0.01 mg/kg.
Test 3
Effect on rhythmic contraction of bladder in anesthetized rat
Test Compound
(5) Methyl 4-[2(R)-[2-(3-chlorophenyl)-2(R)-hydroxyethyl-amino]propyl]phenoxyacetate (This compound was obtained according to a similar manner to that of Example 6 in EP-Al-023385.)
Test Method
Male S.D. rats, aged 7-8 weeks, were anesthetized with urethane (1.2 g/kg, ip) and supine on a board. After a midline incision in the abdomen, the bladder was exposed. Balloon catheter, which was used to measure the intravesical pressure, was inserted into the bladder through a small incision at the apex of the bladder dome. The balloon was then inflated with distilled water and the balloon port of the catheter was connected to pressure transducer. Rhythmic contraction of bladder induced by increase intravesical pressure to 10 mmHg. The test compound was administered intravenously via femoral vein.
The test compound (5) decreased in contractile force of bladder at a dose of 0.1 mg/kg.
Suitable salt of the compounds in the present invention is a pharmaceutically acceptable and conventional non-toxic salt, and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
The compounds in the present invention can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, high-performance liquid chromatography (HPLC), reprecipitation, desalting resin column chromatography, or the like.
The compound in the present invention may be obtained as its hydrate, and its hydrate is included within the scope of present invention.
It is to be noted that each of the compounds in the present invention may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and the mixture thereof are included within the scope of the present invention.
The compounds in the present invention or a salt thereof include solvated compound [e.g., enclosure compound (e.g., hydrate, etc.)].
The compounds in the present invention or a salt thereof include both its crystal form and non-crystal form.
It should be understood that the compounds in the present invention may include the prodrug form.
This application is based on applications No. PP2826/98 and PP5058/98 filed in Australia, the content of which is incorporated hereinto by reference.
The compounds in the present invention may be obtained by methods exemplified by EP-A2-659737, U.S. Pat. No. 5,561,142, EP-A1-211721, EP-A1-023385, or WO97/25311.
The patent, patent applications and publications cited herein are incorporated by reference.
The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound in the present application or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (copical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
The compound or a salt thereof in the present invention is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the diseases.
The pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.
For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation.
While the dosage of therapeutically effective amount of the compound in the present invention varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-100 mg of the compound in the present invention per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.01-100 mg of the compound in the present invention per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.01-200 mg of the compound in the present invention per kg weight of a human being or an animal is generally given for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal.
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1
Under nitrogen, a solution of N-benzyl-(3-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (2.0 g) in tetrahydrofuran (20 ml) was added di-tert-butyl dicarbonate (1.4 g) at 5xc2x0 C., and the solution was stirred at room temperature for 2.5 hours. The resulting solution was evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (2.58 g).
NMR (CDCl3, xcex4): 1.29 (3H, t, J=7.1 Hz), 1.08-1.63 (11H, m), 1.87-2.18 (3H, m), 2.50-2.70 (3H, m), 3.17-3.35 (1H, m), 4.27 (2H, q, J=7.1 Hz), 4.37-4.70 (2H, m), 4.55 (2H, s), 6.60 (1H, dd, J=2.5 and 8.1 Hz), 6.93 (1H, d, J=8.3 Hz), 7.19-7.83 (4H, m)
Preparation 2
To a solution of [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (2.5 g) in ethanol (25 ml) was added 1N sodium hydroxide aqueous solution at 5xc2x0 C., and the solution was stirred at room temperature for 1 hour. The resulting solution was evaporated in vacuo to afford sodium [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetate (2.35 g).
NMR (CDCl3, xcex4): 1.04-1.60 (10H, m), 1.75-2.11 (3H, m), 2.41-2.67 (4H, m), 3.15-3.55 (1H, m) , 4.05 (2H, s), 4.27-4.65 (2H, m), 6.52 (2H, d, J=7.9 Hz), 6.88 (1H, d, J=8.2 Hz), 7.12-7.42 (5H, m)
Preparation 3
Under nitrogen, to a mixture of sodium [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetate (0.50 g) in dichloromethane (5 ml) were added 4N hydrogenchloride in ethyl acetate (0.28 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.24 g), aniline (112 xcexcl) and a catalytic amount of 4-dimethylaminopyridine at 5xc2x0 C., and the mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into 1N hydrogen chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford N-benzyl-N-tert-butoxycarbonyl-(3-N-phenylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.47 g)
NMR (CDCl3, xcex4): 1.13-1.75 (11H, m), 1.90-2.25 (3H, m), 2.50-2.80 (3H, m), 3.24-3.38 (1H, m), 4.27-4.78 (2H, m), 4.53 (2H, s), 6.68 (1H, dd, J=2.5 and 8.1 Hz), 6.98 (1H, d, J=8.3 Hz), 7.12-7.43 (9H, m), 7.58-7.65 (2H, m)
The following compound was obtained according to a similar manner to that of Preparation 3.
Preparation 4
N-Benzyl-N-tert-butoxycarbonyl-(3-N-butylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine
NMR (CDCl3, xcex4): 0.93 (3H, t, J=7.2 Hz), 1.10-2.20 (17H, m), 2.50-2.75 (3H, m), 3.15-3.45 (4H, m), 4.28-4.77 (2H, m), 4.40 (2H, s), 6.60 (2H, dd, J=2.4 and 8.1 Hz), 6.95 (1H, d, J=8.3 Hz), 7.25-7.50 (5H, m)
Preparation 5
Under nitrogen, 4N hydrogenchloride in ethyl acetate (4 ml) was added to N-benzyl-N-tert-butoxycarbonyl-(3-N-phenylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.45 g) at room temperature, and the solution was stirred at the same temperature for 3.5 hours. The resulting solution was evaporated in vacuo. The residue was dissolved in a mixture of saturated aqueous sodium bicarbonate solution and ethyl acetate. After separation, the organic layer was dried over magnesium sulfate and evaporated in vacuo to afford 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-phenylacetamide (346 mg).
NMR (CDCl3, xcex4): 1.38-1.62 (1H, m), 1.63-2.14 (4H, m), 2.65-2.82 (3H, m), 2.90-2.98 (2H, m), 3.82 (2H, ABq, J=3.7 and 12.7 Hz), 4.58 (2H, s), 6.71 (1H, dd, J=2.7 and 8.2 Hz), 6.82 (1H, d, J=2.7 Hz), 7.04 (1H, d, J=8.2 Hz), 7.13-7.42 (8H, m), 7.56-7.65 (2H, m)
MASS (m/z) 401 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 5.
Preparation 6
2-(8-Benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-butylacetamide
NMR (CDCl3, xcex4): 0.92 (3H, t, J=7.2 Hz), 1.25-1.61 (4H, m), 1.73-2.30 (4H, m), 2.63-3.05 (5H, m), 3.34 (2H, q, J=6.9 Hz), 3.85 (2H, ABq, J=13.1 and 17.0 Hz), 4.45 (2H, s), 6.64 (1H, dd, J=2.7 and 8.2 Hz), 7.01 (1H, d, J=8.2 Hz), 7.20-7.45 (5H, m)
MASS (m/z): 381 (M+H)+
Preparation 7
A solution of N-benzyl-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (194 mg) and di-tert-butyl dicarbonate (174 mg) in tetrahydrofuran (2 ml) was stirred at room temperature for 20 hours and partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel (5.8 g) to afford N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine as a pale yellow solid (196 mg).
mp: 150-156xc2x0 C. (dec.)
IR (KBr): 3348 (br), 1666, 1246 cmxe2x88x921 
NMR (DMSO-d6, xcex4): 1.2-1.6 (10H, m), 1.96 (3H, m), 2.49-2.7 (3H, m), 3.10-3.85 (2H, m), 4.30-4.7 (2H, m), 6.46-6.54 (2H, m), 6.77 (1H, m), 7.15-7.36 (5H, m)
(+) API-ES MASS (m/z): 390 (M++Na)
Preparation 8
A solution of N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) was refluxed for 28 hours, cooled to room temperature, and partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene -ethyl acetate) over silica gel (3.6 g) to afford N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (139 mg) as a colorless gum.
IR (KBr): 3411 (br) , 3263 (br) , 1655, 1252 cmxe2x88x921 
Preparation 9
A mixture of N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (135 mg) and 4N hydrogen chloride in ethyl acetate (3 ml) was stirred under ice-cooling for 2 hours and at room temperature for 5 hours and evaporated in vacuo. The residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford N-benzyl-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)amine (100 mg) as a yellow gum.
IR (KBr): 3419 (br), 1238 cmxe2x88x921 
NMR (CDCl3, xcex4): 1.48-1.59 (1H, m), 1.71-2.03 (3H, m), 2.3-3.16 (6H, m), 3.78 (1H, d, J=13.0 Hz), 3.87 (1H, d, J=13.0 Hz), 6.73 (1H, s), 7.08 (1H, s), 7.15-7.32 (6H, m)
Preparation 10
Under nitrogen, to a suspension of sodium hydride (60% in oil, 47 mg) in N,N-dimethylformamide (3 ml) was dropwise added 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (300 mg) in N,N-dimethylformamide (2 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added n-propyl bromide (0.10 ml), and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate =50:1 to 30:1) to give N-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (278 mg)
(+) ESI-MASS (m/z): 310 (M+H)+
The following compounds [Preparation 11 and 12] were obtained according to a similar manner to that of Preparation 10.
Preparation 11
N-Benzyl-(3-hexyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine
(+) APCI-MASS (m/z) 352 (M+H)+
Preparation 12
N-Benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine
NMR (CDCl3, xcex4): 1.2-1.6 (2H, m), 1.7-2.1 (3H, m), 2.6-2.95 (5H, m), 3.7-3.9 (2H, m), 5.03 (2H, s), 6.70 (1H, dd, J=2.7 and 8.2 Hz), 6.83 (1H, d, J=2.6 Hz), 6.98 (1H, d, J=8.2 Hz), 7.2-7.5 (10H, m)
Preparation 13
Under nitrogen, a solution of (2S)-1-[N-benzyl-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (20 g), chlorotriethylsilane (7.4 ml), imidazole (3.2 g) and 4-dimethylaminopyridine (0.48 g) in N,N-dimethylformamide (200 ml) was stirred at room temperature for 12 hours. The resulting mixture was poured into water, and extracted with ethyl acetate-hexane (1:1). The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amine (25 g).
(+) ESI-MASS (m/z): 622 (M+H)+
Preparation 14
A mixture of N-benzyl-N-(3-benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amine (25 g) and 10% palladium on activated carbon (50% wet, 2.5 g) in methanol (250 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours. After filtration, the filtrate was evaporated in vacuo to give 8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (17 g).
(+) APCI-MASS (m/z): 442 (M+H)+
Preparation 15
Under nitrogen, a mixture of 8-[(2S)-3-phenoxy-2-(triethylsilyloxy)propylamino] -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (17 g) and di-tert-butyl dicarbonate (9.5 g) in tetrahydrofuran (180 ml) was stirred at room temperature for 18 hours. After evaporation, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate =20:1 to 10:1) to give N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (17 g).
(+) APCI-MASS (m/z): 442 (Mxe2x88x92Boc+2H)+
Preparation 16
Under nitrogen, to a suspension of sodium hydride (60% in oil, 12 mg) in N,N-dimethylformamide (2 ml) was dropwise added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in N,N-dimethylformamide (1 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added ethyl iodide (27 xcexcl), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give N-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (130 mg).
NMR (CDCl3, xcex4): 0.55-0.75 (6H, m), 0.9-1.0 (9H, m), 1.2-1.55 (4H, m), 1.48 (9H, m), 1.9-2.2 (3H, m), 2.55-2.9 (3H, m), 3.1-3.65 (4H, m), 3.85-4.1 (4H, m), 4.2-4.4 (1H, m), 6.55-6.7 (2H, m), 6.85-7.0 (4H, m), 7.2-7.3 (2H, m)
(+) ESI-MASS (m/z): 592 (M+Na)+
The following compound was obtained according to a similar manner to that of Preparation 16.
Preparation 17
N-(3-Allyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine
NMR (DMSO-d6, xcex4): 0.55-0.75 (6H, m), 0.8-1.1 (9H, m), 1.2-1.6 (1H, m), 1.48 (9H, m), 1.9-2.2 (3H, m), 2.6-2.9 (2H, m), 3.15-3.7 (4H, m), 3.8-4.05 (2H, m), 4.25-4.5 (3H, m), 5.25-5.45 (2H, m), 5.95-6.15 (1H, m), 6.6-6.75 (2H, m), 6.8-7.0 (4H, m), 7.25-7.3 (2H, m)
Preparation 18
Under nitrogen, to dimethylsulfoxide (3 ml) was added potassium hydroxide (31 mg) at room temperature, and the suspension was stirred at the same temperature for 1 hour. To this one were added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) and isopropyl bromide (78 xcexcl), and the mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into aqueous 10% sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate =20:1) to give N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (96 mg).
(+) APCI-MASS (m/z): 326 (Mxe2x88x92Boc+2H)+
The following compounds [Preparations 19 to 21] were obtained according to a similar manner to that of Preparation 18.
Preparation 19
N-(3-Benzyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine
(+) APCI-MASS (m/z): 532 (Mxe2x88x92Boc+2H)+
Preparation 20
N-Benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine
(+) APCI-MASS (m/z): 370 (Mxe2x88x92Boc+2H)+
Preparation 21
N-Benzyl-N-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine
(+) APCI-MASS (m/z): 316, 318 (Mxe2x88x92Boc+2H)+
Preparation 22
Under nitrogen, to a solution of N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in tetrahydrofuran (5 ml) was added triphenylphosphine (290 mg), cyclopentanol (60 xcexcl) and diethyl azodicarboxylate (174 xcexcl) at 5xc2x0 C., and the mixture was stirred at the same temperature for 5.5 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give N-(3-cyclopentyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (108 mg).
(+) APCI-MASS (m/z): 510 (Mxe2x88x92Boc+2H)+
The following compound was obtained according to a similar manner to that of Preparation 22.
Preparation 23
N-(3-Phenethyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl-tert-butoxycarbonylamine
(+) APCI-MASS (m/z): 546 (Mxe2x88x92Boc+2H)+
Preparation 24
Under nitrogen, to a suspension of potassium carbonate (76 mg) in a mixture of acetonitrile (5 ml) and N,N-dimethylformamide (2 ml) was added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) at room temperature. After being stirred at the same temperature for 30 minutes, to this one was an excessive amount of bromofluoromethane, and the mixture was stirred for 12 hours. The resulting solution was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1) to give N-(3-fluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (130 mg).
(+) APCI-MASS (m/z): 474 (Mxe2x88x92Boc+2H)+
Preparation 25
Under nitrogen, to a solution of N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in dichloromethane (5 ml) were added pyridine (64 ml), 4-nitrophenyl chloroformate (116 mg) and a catalytic amount of 4-dimethylaminopyridine at 5xc2x0 C. After being stirred at the same temperature for 2 hours, to this one was added about 6.8M ammonia in ethanol (0.5 ml), and the mixture was stirred at room temperature for 12 hours. The resulting mixture was pured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give N-[(2S)-3-phenoxy-2-(triethyl-silyloxy)propyl]-N-[3-carbamoyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (129 mg).
(+) APCI-MASS (m/z): 485 (Mxe2x88x92Boc+2H)+
Preparation 26
Under nitrogen, a mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (7.7 g) and di-tert-butyl dicarbonate (6.9 g) in tetrahydrofuran (80 ml) was stirred at room temperature for 12 hours. After evaporation, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=7:1) to give N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (10 g).
NMR (CDCl1, xcex4): 1.1-1.7 (10H, m), 1.85-2.1 (3H, m), 2.45-2.7 (3H, m), 3.15-3.85 (2H, m), 4.3-4.7 (2H, m), 5.05-5.25 (1H, m), 6.3-6.6 (2H, m), 6.86 (2H, d, J=8.1 Hz), 7.15-7.4 (6H, m)
Preparation 27
To N-benzyl-N-[3-(3-cyanopyridin-2-yloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (480 mg) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by being made basic with saturated aqueous sodium hydrogencarbonate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)oxy-3-cyanopyridine (339 mg).
(+) APCI-MASS (m/z): 370 (M+H)+
The following compounds [Preparations 28 to 30] were obtained according to a similar manner to that of Preparation 27.
Preparation 28
N-Benzyl- [3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]amine
(+) APCI-MASS (m/z): 326 (M+H)+
Preparation 29
N-Benzyl-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine
(+) APCI-MASS (m/z): 328 (M+H)+
Preparation 30
N-Benzyl-(2-chloro-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine
(+) APCI-MASS (m/z): 316, 318 (M+H)+
Preparation 31
Under nitrogen, to dimethylsulfoxide (5 ml) was added potassium hydroxide (34 mg) at room temperature, and the suspension was stirred at the same temperature for 40 minutes. To this one were added N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (200 mg) and 2-chloroethyl methyl ether (55 xcexcl), and the mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give N-benzyl-N-[3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (213 mg).
(+) APCI-MASS (m/z): 326 (Mxe2x88x92Boc+2H)+
Preparation 32
A solution of 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetic acid ethyl ester (320 mg) and 28% ammonium hydroxide (1 ml) in methanol (3 ml) was stirred at room temperature for 12 hours. The mixture was evaporated in vacuo to give 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetamide (270 mg).
(+) APCI-MASS (m/z): 325 (M+H)+
Preparation 33
Under nitrogen, to a suspension of sodium hydride (60% in oil, 300 mg) in N,N-dimethylformamide (20 ml) was added N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (2.5 g) in N,N-dimethylformamide (25 ml) at 5xc2x0 C. After being stirred at room temperature for 30 minutes, to this one were added ethyl bromoacetate (0.75 ml) and tetra-n-butylammonium bromide (1.1 g) at 5xc2x0 C., and the mixture was stirred at room temperature for 32 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (1.6 g).
NMR (CDCl3, xcex4): 1.1-1.7 (10H, m), 1.30 (3H, t, J=7.1 Hz), 1.85-2.2 (3H, m), 2.5-2.7 (3H, m), 3.2-3.4 (1H, m), 4.27 (2H, q, J=7.2Hz), 4.3-4.7 (2H, m), 4.54 (2H, s), 6.4-6.65 (2H, m), 6.93 (1H, d, J=8.3 Hz), 7.2-7.4 (5H, m)
(+) APCI-MASS (m/z): 354 (Mxe2x88x92Boc+2H)+
Preparation 34
To a solution of 2-[8-(N-benzyl-N-tert-butoxycarbonyl-amino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (1.6 g) in ethanol (16 ml) was added aqueous iN sodium hydroxide at 5xc2x0 C., and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was dissolved into a mixture of aqueous 0.1N hydrochloric acid and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated with hexane and dried in vacuo to give 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (1.3 g).
NMR (DMSO-d6, xcex4): 1.1-1.7 (10H, m), 1.75-2.2 (3H, m), 2.45-2.7 (1H, m), 3.15-3.75 (4H, m), 4.3-4.7 (2H, m), 4.57 (2H, s), 6.4-6.7 (2H, m), 6.96 (1H, d, J=8.2 Hz), 7.2-7.5 (5H, m), 12.9 (1H, br s)
(+) APCI-MASS (m/z) 326 (Mxe2x88x92Boc+2H)+
Preparation 35
Under nitrogen, a solution of 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (300 mg) in dichloromethane (3 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg), dimethylamine hydrochloride (63 mg) and 4-dimethylaminopyridine (130 mg) at 5xc2x0 C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into 0.1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give N-benzyl-N-(3-N,N-dimethylcarbamoylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (312 mg).
NMR (CDCl3, xcex4) 1.1-1.65 (10H, m), 1.85-2.15 (3H, m), 2.5-2.7 (4H, m), 2.98 (3H, s), 3.08 (3H, s), 3.2-3.45 (1H, m), 4.5-4.7 (2H, m), 4.60 (2H, s), 6.45-6.7 (2H, s), 6.93 (1H, d, J=8.2 Hz), 7.2-7.4 (5H, m)
(+) APCI-MASS (m/z) 353 (Mxe2x88x92Boc+2H)+
Preparation 36
To N-benzyl-N-(3-N,N-dimethylcarbamoylmethoxy-6,7,8,9-tetrahdyro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (279 mg) was added 4N hydrogen chloride in ethyl acetate (3 ml), and the mixture was stirred at room temperature for 1.5 hours. After evaporation in vacuo, the residue was dissolved into saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by separation. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. A mixture of the residue and 10% palladium on activated carbon (50% wet, 100 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 7 hours. After filtration, the filtrate was evaporated in vacuo to give 2-(8-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N,N-dimethylacetamide (137 mg).
NMR (CDCl3, xcex4) 1.4-2.1 (4H, m), 2.65-3.15 (5H, m), 2.98 (3H, m), 3.09 (3H, s), 4.65 (2H, s), 6.68 (1H, dd, J=2.7 and 8.1 Hz), 6.77 (1H, d, J=2.7 Hz), 6.98 (1H, d, J=8.2 Hz)
(+) APCI-MASS (m/z): 263 (M+H)+
Preparation 37
Under nitrogen, to a solution of 3-nitro-5,7,8,9-tetrahydrobenzocyclohepten-6-one (300 mg) in 1,2-dichloroethane (10 ml) were added benzylamine (0.24 ml), sodium triacetoxyborohydride (460 mg) and acetic acid (0.17 ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The resulting mixture was poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:5) to give N-benzyl-(3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (342 mg).
(+) APCI-MASS (m/z): 297 (M+H)+
The following compound was obtained according to a similar manner to that of Preparation 37.
Preparation 38
N-Benzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-amine
(+) APCI-MASS (m/z): 252 (M+H)+
Preparation 39
Under nitrogen, to the solution of 1-tetralone (16 g) in dichloromethane (80 ml) were added zinc(II) iodide (0.69 g) and trimethylsilyl cyanide (15 g) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give crude 1-(trimethylsilyloxy)-1-cyano-1,2,3,4-tetrahydronaphthalene (27 g), which was successively used in the next reaction.
The following compounds [Preparations 40 and 41] were obtained according to a similar manner to that of Preparation 39.
Preparation 40
7-Methyl-1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene
Preparation 41
7-Chloro-1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene
Preparation 42
Under nitrogen, to the suspension of lithium aluminum hydride (8.4 g) in tetrahydrofuran (120 ml) was dropwise added 1-trimethylsilyloxy-1-cyano-1,2,3,4-tetrahydronaphthalene (27 g) in tetrahydrofuran (120 ml) at 5xc2x0 C., and the mixture was stirred at room temperature for 24 hours. To the mixture were added sodium fluoride (37 g) and water (12 ml) at 5xc2x0 C., and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitate was removed by filtration. The filtrate was evaporated in vacuo to give 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g)
(+) APCI-MASS (m/z): 178 (M+H)+
The following compounds [Preparations 43 and 44] were obtained according to a similar manner to that of Preparation 42.
Preparation 43
1-Aminomethyl-7-chloro-1-hydroxy-1,2,3,4-tetrahydronaphthalene
NMR (CDCl3, xcex4): 1.8-2.2 (4H, m), 2.6-2.95 (4H, m), 7.00 (1H, d, J=8.2 Hz), 7.13 (1H, dd, J=2.3 and 8.2 Hz), 7.52 (1H, d, J=2.2 Hz)
Preparation 44
1-Aminomethyl-7-methyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene
NMR (CDCl3, xcex4): 1.5-2.2 (7H, m), 2.31 (3H, s), 2.6-2.9 (4H, m), 6.9-7.05 (2H, m), 7.32 (1H, s)
Preparation 45
To a solution of 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g) in 10% acetic acid in water (380 ml) was dropwise added sodium nitrite (11 g) in water (56 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was diluted with ethyl acetate and separated. The organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified. by column chromatography on silica gel (hexane-ethyl acetate) to give 5,7,8,9-tetrahydrobenzocyclohepten-6-one (9.3 g).
(+) APCI-MASS (m/z): 161 (M+H)+
The following compounds [Preparations 46 and 47] were obtained according to a similar manner to that of Preparation 45.
Preparation 46
3-Chloro-5,7,8,9-tetrahydrobenzocyclohepten-6-one
NMR (CDCl3, xcex4): 1.9-2.1 (2H, m), 2.57 (2H, t, J=7.0 Hz), 2.9-3.0 (2H, m), 3.68. (2H, s), 7.09 (1H, d, J=7.8 Hz), 7.16 (1H, s), 7.18 (1H, d, J=7.8 Hz)
Preparation 47
3-Methyl-5,7,8,9-tetrahydrobenzocyclohepten-6-one
NMR (CDCl3, xcex4): 1.9-2.05 (2H, m), 2.30 (3H, s), 2.57 (2H, t, J=6.8 Hz), 2.85-2.95 (2H, m), 3.69 (2H, s), 6.95-7.1 (3H, m)
Preparation 48
A stirred solution of (2S)-1-phenoxy-2,3-epoxypropane (1.0 g) and concentrated ammonium hydroxide (10 ml) in ethanol (10 ml) was sealed up at room temperature for 12 hours. The mixture was evaporated in vacuo and dried to give (2S)-1-amino-3-phenoxy-2-propanol (1.1 g).
(+) APCI-MASS (m/z): 168 (M+H)+
Preparation 49
To a mixture of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (1.01 g), 2,6-lutidine (0.38 ml) and N,N-dimethylaminopyridine (0.067 g) in dichloromethane (20 ml) was added dropwise trifluoromethanesulfonic anhydride (0.51 ml) at xe2x88x9230xc2x0 C. The mixture was warmed to room temperature over 3 hours and then washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (20:1) to afford N-benzyl-N-tert-butoxycarbonyl-(3-trifluoromethylsulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.98 g).
NMR (DMSO-d6, xcex4): 1.14-1.50 (11H, m), 1.80-2.15 (3H, m), 2.60-2.80 (3H, m), 3.30-3.60 (1H, m), 4.25-4.62 (2H, m), 6.98-7.50 (8H, m)
(+) ESI-MASS (m/z): 522 (M+Na)+
Preparation 50
To a suspension of N-benzyl-N-tert-butoxycarbonyl-(3-trifluoromethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (500 mg) in toluene (6 ml) and water (2 ml) were added phenylboronic acid (122 mg), sodium carbonate (210 mg) and tetrakis(triphenylphosphine)palladium(0) (35 mg), and the mixture was stirred at 80xc2x0 C. for 3.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=30:1 to 20:1) to give N-benzyl-N-(3-phenyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (494 mg).
(+) ESI-MASS (m/z): 450 (M+Na)+
Preparation 51
Under nitrogen, a suspension of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (300 mg) and N-chlorosuccinamide (110 mg) in 1,4-dioxane (5 ml) was stirred at 10020  C. for 9 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene:ethyl acetate=50:1 to 10:1) to give N-benzyl-N-(2-chloro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (152 mg) .
(+) APCI-MASS (m/z): 302, 304 (Mxe2x88x92Boc+2H)+
Preparation 52
Under nitrogen, to a solution of (2R)-1-tosyloxy-2,3-epoxypropane (3.0 g) in tetrahydrofuran (30 ml) were added N,N-diisopropylethylamine (2.5 ml) and thiophenol (1.3 ml) at 5xc2x0 C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give (2S)-3-phenylthio-1-tosyloxy-2-propanol (3.9 g).
NMR (CDCl3, xcex4): 2.44 (3H, m), 2.75-3.25 (3H, m), 3.85-4.3 (3H, m), 7.15-7.4 (7H, m), 7.7-7.8 (2H, m)
Preparation 53
Under nitrogen, to a solution of (2S)-3-phenylthio-1-tosyloxy-2-propanol (3.9 g) in ethanol (40 ml) was added 20% sodium methoxide in ethanol (4.7 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 30 minutes. After being filtrated off to remove precipitates, the filtrate was concentrated in vacuo. The residue was dissolved into a mixture of aqueous 0.1N sodium hydroxide and diethyl ether. After separation, the organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give (2S)-1-phenylthio-2,3-epoxypropane (1.5 g).
(+) APCI-MASS (m/z): 167 (M+H)+
Preparation 54
Under nitrogen, to a solution of allylphenylamine (3 ml) in dichloromethane (30 ml) were added pyridine (2.1 ml) and benzyl chloroformate (3.5 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into aqueous 1N hydrogen chloride and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1 to 10:1) to give N-allyl-N-phenylbenzyloxycarbonylamine (5.5 g).
(+) APCI-MASS (m/z): 268 (M+H)+
Preparation 55
Under nitrogen, to a solution of N-allyl-N-phenyl-benzyloxycarbonylamine (5.5 g) in dichloromethane (50 ml) was added m-chloroperbenzoic acid (3.9 g) at 5xc2x0 C., and the mixture was stirred at room temperature for 3 days. The resulting mixture was poured into aqueous sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give 1-(N-benzyloxycarbonyl-N-phenylamino)-2,3-epoxypropane (2.2 g).
(+) APCI-MASS (m/z): 284 (M+H)+
Preparation 56
To a suspension of but-3-butenylbenzene (3 ml) and sodium hydrogen carbonate (2.5 g) in a mixture of dichloromethane (200 ml) and water (60 ml) was added small portions of m-chloroperbenzoic acid (3.5 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. After separation, the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:3) to give 2-phenethyloxirane (970 mg).
NMR (CDCl3, xcex4): 1.7-1.9 (2H, m), 2.45-2.5 (1H, m), 2.7-3.0 (4H, m), 7.1-7.4 (5H, m)
Preparation 57
A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-5 benzocyclohepten-6-yl)amine (1.0 g) and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5.5 hours. After filtration, the filtrate was evaporated in vacuo to give 3-methoxy-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (720 mg).
NMR (CDCl3, xcex4): 1.4-1.6 (1H, m), 1.7-2.0 (2H, m), 2.1-2.3 (1H, m), 2.7-2.75 (2H, m), 2.85-3.3 (3H, m), 3.76 (3H, s), 6.66 (1H, dd, J=2.7 and 8.2 Hz), 6.76 (1H, d, J=2.6 Hz), 7.00 (1H, d, J=8.2 Hz)
The following compounds [Preparation 58 and 59] were obtained according to a similar manner to that of Preparation 57.
Preparation 58
2-(8-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)acetic acid tert-butyl ester
NMR (CDCl3, xcex4) 1.3-2.1 (4H, m), 1.49 (9H, s), 2.65-3.1 (5H, m), 4.48 (2H, m), 6.61 (1H, dd, J=2.7 and 8.2 Hz), 6.73 (1H, d, J=2.7 Hz), 6.98 (1H, d, J=8.2 Hz)
Preparation 59
2-(8-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-N-phenylacetamide
NMR (CDCl3, xcex4): 1.45-2.15 (4H, m), 2.7-3.1 (5H, m), 4.58 (2H, m), 6.72 (1H, dd, J=2.7 and 8.2 Hz), 6.83 (1H, d, J=2.7 Hz), 7.04 (1H, d, J=8.2 Hz), 7.1-7.25 (1H, m), 7.3-7.4 (2H, m), 7.55-7.7 (2H, m), 8.30 (1H, br s)
(+) ESI-MASS (m/z): 311 (M+H)+
Preparation 60
To a solution of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (500 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by being made basic with saturated aqueous sodium hydrogencarbonate. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give crude 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol.
Under nitrogen, to a suspension of sodium hydride (60% in oil, 60 mg) in N,N-dimethylformamide (3 ml) was added above obtained one in N,N-dimethylformamide (4 ml) at 5xc2x0 C. After being stirred at room temperature for 30 minutes, to this one were added tert-butyl bromoacetate (0.22 ml) and tetra-n-butylammonium bromide (220 mg) at 5xc2x0 C., and the mixture was stirred at room temperature for 6 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1 to 20:1) to give 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy) acetic acid tert-butyl ester (474 mg)
(+) APCI-MASS (m/z): 382 (M+H)+
Preparation 61
A mixture of 6-(4-nitrophenylazo)pyridin-3-ol (300 mg) and 20% palladium hydroxide on carbon (60 mg) in a mixture of acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 70 minutes. After filtration, the filtrate was evaporated in vacuo. Under nitrogen, to a mixture of the residue in dichloromethane (10 ml) was added bis(trimethylsilyl)acetamido (6.0 ml) at 5xc2x0 C. After being stirred at room temperature for 30 minutes, to this one was added benzyl chloroformate (0.54 ml) at 5xc2x0 C., and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the residue was added chloroform, and insoluble materials were filtered off. After the filtrate was evaporated in vacuo, the residue was purified by column chromatography on silica gel (chloroform:methanol=50:1 to 20:1), followed by crystallization from toluene-methanol to give 2-benzyloxy-carbonylamino-5-hydroxypyridine (159 mg).
(+) APCI-MASS (m/z): 245 (M+H)+
Preparation 62
Under nitrogen, to a suspension of sodium hydride (60% in oil, 189 mg) in N,N-dimethylformamide (20 ml) was dropwise added 2-benzyloxycarbonylamino-5-hydroxypyridine (1.1 g) in N,N-dimethylformamide (12 ml) at 5xc2x0 C., and the mixture was stirred at room temperature for 1 hour. To this one was added (2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.1 g) at 5xc2x0 C., and the mixture was stirred at room temperature for 7 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=9:1) to give 2-benzyloxycarbonylamino-5-[(2S)-oxiranylmethoxy]pyridine (780 mg).
(+) APCI-MASS (m/z): 301 (M+H)+
Preparation 63
To a mixture of 8-methoxy-1-tetralone (2.66 g) and zinc iodide (0.096 g) in dichloromethane (13 ml) was dropwise added trimethylsilylcyanide (2.65 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight and then poured into a saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (4:1) to afford 1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.64 g).
NMR (DMSO-d6, xcex4): 0.15 (9H, s), 1.70-1.81 (2H, m), 2.09-2.38 (2H, m), 2.70-2.77 (2H, m), 3.84 (3H, s), 6.76 (1H, d, J=8.0 Hz), 6.92 (1H, d, J=8.0 Hz), 7.29 (1H, d, J=8.0, 8.0 Hz)
(+) ESI-MASS (m/z): 298 (M+Na)+
Preparation 64
To a mixture of lithiumaluminumhydride (0.99 g) in tetrahydrofuran (18 ml) was added dropwise a solution of 1-cyano-8-methoxy-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene (3.59 g) in tetrahydrofuran (18 ml) under ice-cooling and a nitrogen atmosphere. After stirring at room temperature for 3 hours, sodium fluoride (1.09 g) and water (1.41 ml) were added to the reaction mixture under ice-cooling. After stirring for additional 30 minutes, insoluble materials were filtered off and washed with 5% ethanol in ethyl acetate. The filtrate was evaporated in vacuo to afford 1-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.60 g), which was used in the next step without purification.
NMR (DMSO-d6, xcex4): 1.38-1.72 (3H, m), 2.07-2.14 (1H, m), 2.62-2.91 (6H, m), 3.77 (3H, s), 6.68 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=7.8 Hz), 7.09 (1H, dd, J=7.8, 7.8 Hz)
(+) ESI-MASS (m/z): 190 (Mxe2x88x92OH)+
Preparation 65
To a suspension of l-aminomethyl-1-hydroxy-8-methoxy-1,2,3,4-tetrahydronaphthalene (2.54 g) in 10% acetic acid was added dropwise a solution of sodium nitrite (1.27 g) in water (6.4 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1) to afford 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (1.08 g).
NMR (DMSO-d6, xcex4): 1.77-1.91 (2H, m), 2.47 (2H, t, J=7.0 Hz), 2.85-2.92 (2H, m), 3.76 (3H, s), 3.76 (2H, s), 6.76 (1H, d, J=7.5 Hz), 6.88 (1H, d, J=7.5 Hz), 7.16 (1H, dd, J=7.5 and 7.5 Hz)
(+) ESI-MASS (m/z): 213 (M+Na)+
Preparation 66
A solution of 4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (500 mg) and benzylamine (0.29 ml) in the presence of catalytic amounts of p-toluenesulfonic acid monohydrate in toluene (5 ml) was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the solution of the residue in methanol (5 ml) was added sodium borohydride (99 mg) under nitrogen at 5xc2x0 C., and the mixture was stirred at room temperature for 12 hours. After the resulting mixture was evaporated in vacuo, the residue was dissolved into ice-cold water and ethyl acetate. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 1:1) to give N-benzyl-(4-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (660 mg).
NMR (DMSO-d6, xcex4): 1.17-1.37 (1H, m), 1.53-2.02 (3H, m), 2.25-2.38 (1H, m), 2.50-3.80 (3H, m), 3.26-3.32 (2H, m), 3.67-3.86 (2H, m), 3.77 (3H, s), 6.68 (1H, d, J=7.5 Hz), 6.79 (1H, d, J=7.5 Hz), 7.01 (1H, dd, J=7.5 and 7.5 Hz), 7.17-7.30 (5H, m)
(+) ESI-MASS (m/z): 282 (M+H)+
Preparation 67
Into a mixture of N-benzyl-N-(3-trifluoromethyl-sulfonyloxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (0.94 g), palladium acetate (0.084 g), 1,3-bis(diphenylphosphino)propane (0.16 g), triethylamine (0.79 ml) in methanol (2.8 ml) and N,N-dimethylformamide (7 ml) was introduced carbon oxide gas at room temperature for 1 hour. Then the mixture was heated at 75xc2x0 C. for 2.5 hours with carbon oxide gas bubbling. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1) to afford 8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-carboxylic acid methyl ester (0.76 g).
NMR (DMSO-d6, xcex4) 1.13-1.50 (11H, m), 1.79-2.13 (3H, m), 2.58-2.79 (3H, m), 3.44-3.74 (1H, m), 3.83 (3H, s), 4.30-4.62 (2H, m), 7.20-7.38 (6H, m), 7.50-7.60 (1H, m), 7.67 (1H, d, J=7.7 Hz)
(+) ESI-MASS (m/z): 432 (M+Na)+
Preparation 68
To a solution of 8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (10.07 g) in dichloromethane (100 ml) was added trifluoroacetic acid (9.47 ml), and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (7.78 g).
NMR (DMSO-d6, xcex4) 1.24-1.43 (1H, m), 1.59-2.08 (4H, m), 2.42-2.50 (1H, m), 2.76-3.03 (4H, m), 3.75 (2H, d, J=3.1 Hz), 3.83 (3H, s), 7.16-7.36 (6H, m), 7.67 (1H, dd, J=7.7, 1.8 Hz), 7.75 (1H, d, J=1.8 Hz)
(+) ESI-MASS (m/z) 310 (M+H)+
Preparation 69
To a mixture of 8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxpropyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.80 g), imidazole (1.68 g) and catalytic amount of N,N-dimethylaminopyridine in N,N-dimethylformamide (100 ml) was added triethylsilyl chloride (3.82 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (20:1) to afford 8-(N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)-propyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (6.07 g).
NMR (DMSO-d6, xcex4): 0.50-0.67 (6H, m), 0.83-0.95 (9H, m), 1.13-1.37 (1H, m), 1.42 (9H, s), 1.89-2.22 (3H, m), 2.68-2.98 (3H, m), 3.20-3.48 (4H, m), 3.81, 3.83 (total 3H, s), 3.83-3.92 (1H, m), 3.97-4.07 (1H, m), 4.20-4.37 (1H, m), 6.86-6.97 (3H, m), 7.18-7.34 (3H, m), 7.68-7.75 (2H, m)
(+) APCI-MASS (m/z): 484 (Mxe2x88x92Boc+2H)+
Preparation 70
To a cold (xe2x88x9278xc2x0 C.) solution of 8-[N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]amino]-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (5.90 g) in tetrahydrofuran (120 ml) was added dropwise a solution of diisobutylaluminum hydride in hexane (0.95M, 53.2 ml). The reaction mixture was warmed to room temperature over 4 hours, and then saturated sodium bicarbonate solution was added dropwise to the mixture. The resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1) to afford N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxy-carbonylamine (5.20 g).
NMR (DMSO-d6, xcex4): 0.52-0.68 (6H, m), 0.85-0.97 (9H, m), 1.08-1.38 (1H, m), 1.41 (9H, s), 1.80-2.20 (3H, m), 2.50-2.88 (3H, m), 3.15-3.52 (4H, m), 3.80-3.90 (1H, m), 3.94-4.05 (1H, m), 4.22-4.40 (1H, m), 4.41 (2H, d, J=4.5 Hz), 5.06 (1H, t, J=4.5 Hz), 6.83-7.03 (6H, m), 7.30 (2H, dd, J=7.4 and 7.4 Hz)
(+) APCI-MASS (m/z): 456 (Mxe2x88x92Boc+2H)+
Preparation 71
To a mixture of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed successively with water, sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford crude N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (2.18 g) which was used without purification.
Preparation 72
To a solution of N-tert-butoxycarbonyl-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-(3-N,N-dimethylamino-methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl) amine (0.60 g) in tetrahydrofuran (3 ml) was added a solution of dimethylamine in tetrahydrofuran (2M, 1.89 ml) under ice-cooling. The mixture was stirred at room temperature overnight and then partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (50:1 to 20:1) to afford N-(3-N,N-dimethylaminomethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbononylamine (0.41 g).
NMR (DMSO-d6, xcex4): 0.43-0.67 (6H, m), 0.82-0.98 (9H, m), 1.10-1.35 (1H, m), 1.41 (9H, s), 1.81-2.08 (3H, m), 2.11 (6H, s), 2.50-2.90 (3H, m), 3.17-3.58 (5H, m), 3.78-4.22 (4H, m), 6.87-7.04 (6H, m), 7.22-7.34 (2H, m) (0.41 g).
(+) APCI-MASS (m/z): 583 (M+H)+
Preparation 73
A mixture of 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (4.21 g) and sodium methoxide (2.21 g) in formamide (42 ml) was heated at 110xc2x0 C. for 2 hours. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1 to 10:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxamide (2.71 g).
NMR (DMSO-d6, xcex4): 1.24-1.42 (1H, m), 1.59-2.05 (4H, m), 2.40-2.50 (1H, m), 2.70-3.01 (4H, m), 3.67-3.84 (2H, m), 7.13 (1H, d, J=7.7 Hz), 7.18-7.36 (6H, m), 7.59 (1H, dd, J=7.7 and 1.8 Hz), 7.70 (1H, d, J=1.8 Hz), 7.86 (1H, s)
(+) APCI-MASS (m/z): 295 (M+H)+
Preparation 74
To a solution of (R)-4-(3-toluenesulfonyloxy-2-hydroxy)propyl-1-benzyloxybenzene (110 mg) in acetonitrile (10 ml), a solution of nitronium tetrafluoroborate (536 mg) in acetonitrile (10 ml) was added dropwise with ice-bath cooling. The reaction mixture was stirred for 0.5 hour and worked up in a usual manner. The crude product was purified by a column chromatography (SiO2 50 cm3, eluent; 33% ethyl acetate-hexane) to give (R)-1-(3-toluenesulfonyloxy-2-hydroxy)propyl-3-nitro-4-benzyloxybenzene (259 mg) as an oil.
IR (Film) 1623, 1533, 1356, 1267, 1174, 1095, 984, 816 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.17 (1H, d, J=4.4 Hz), 2.46 (3H, s), 2.7-2.8 (2H, m), 3.9-4.2 (3H, m), 5.21 (2H, s), 7.06 (1H, t, J=8.7 Hz), 7.3-7.5 (7H, m), 7.66 (1H, d, J=2.1 Hz), 7.7-7.9 (3H, m)
Preparation 75
To a solution of 4-benzyloxybromobenzene (263 mg) in dry tetrahydrofuran (3 ml), butyllithium (1.54M hexane solution, 0.71 ml) was added dropwise at xe2x88x9278xc2x0 C. under nitrogen, and the resulting mixture was stirred for 30 minutes. To the reaction mixture, boranetrifluoride diethyl ether (123 xcexcl), and a solution of (R)-1-tosyloxy-2,3-epoxypropane (202 mg) in dry tetrahydrofuran (1 ml) were added below xe2x88x9250xc2x0 C. The reaction mixture was worked up in a usual manner and purified by a column chromatography (SiO2 40 cm3, 25% ethyl acetate-hexane) to give (R)-4-(3-toluenesulfonyloxy-2-hydroxy)propyl-1-benzyloxybenzene (144 mg) as an oil.
IR (Film) 1512, 1360, 1240, 1178, 978, 833, 814 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.04 (1H, d, J=4.4 Hz), 2.45 (3H, s), 2.72 (2H, d, J=5.3 Hz), 3.9-4.1 (3H, m), 5.04 (2H, s), 6.89 (2H, d, J=8.7 Hz), 7.06 (2H, d, J=8.7 Hz), 7.3-7.5 (7H, m), 7.7-7.9 (3H, m)
Preparation 76
A mixture of (R)-1-(3-toluenesulfonyloxy-2-hydroxy)propyl-3-nitro-4-benzyloxybenzene (26 mg), iron powder, ammonium chloride (2.6 mg) and wet ethanol (0.5 ml) was heated at 80xc2x0 C. for 1 hour and 20 minutes, filtered and worked up in the usual manner. The residue was treated with small amounts of potassium carbonate in methanol and worked up in the usual manner to give epoxide. The crude epoxide was dissolved in dichloromethane, treated with triethylamine followed by methanesulfonyl chloride, worked up in the usual manner and purified by preparative TLC (SiO2, 50% ethyl acetate-hexane) to give (R)-1-(3-methanesulfonylamino-4-benzyloxy)phenyl-2,3-epoxypropane (10.8 mg) as an oil.
IR (Film) 2931, 1612, 1508, 1365, 1321, 1270, 1160, 975, 924 cmxe2x88x921 
NMR (CDCl3, xcex4): 2.50 (1H, dd, J=2.6 and 4.9 Hz), 2.7-3.0 (3H, m), 2.89 (3H, s), 3.1-3.2 (1H, m), 5.14 (2H, s), 7.02 (1H, d, J=8.4 Hz), 7.24 (1H, dd, J=2.2 and 9.6 Hz), 7.3-7.6 (6H, m)
Preparation 77
Under nitrogen, to a solution of 4-acetylaminophenol (569 mg) and sodium hydride (150 mg) in N,N-dimethylformamide (30 ml) was added (2S)-(+)-1-tosyloxy-2,3-epoxypropane (1.0 g) at 0xc2x0 C., and the mixture was stirred at the same temperature for 0.5 hour. The mixture was allowed to warm to room temperature and stirred for 3 hours at this temperature. The resulting mixture was poured into 10% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-(4-acetylamino)phenoxy-2,3-epoxypropane (285 mg).
(+) APCI-MASS (m/z): 149 (M+Na)+
Preparation 78
Under nitrogen, to a solution of 2,3-dimethylbenzene-1,4-diol (25.0 g) and potassium hydroxide (40.6 g) in dimethylsulfoxide (100 ml) was added iodomethane (17 ml) at room temperature, and the mixture was stirred for 3 hours at this temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 1,4-dimethoxy-2,3-dimethylbenzene (23.16 g).
(+) APCI-MASS (m/z): 167 (M+H)+
Preparation 79
A solution of 1,4-dimethoxy-2,3-dimethylbenzene (23.16 g), benzoyl peroxide (673 mg) and N-bromosuccinimide (52.0 g) in carbontetrachloride (140 ml) was refluxed for 4 hours and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2,3-dibromomethyl-1,4-dimethoxybenzene (8.17 g).
(+) APCI-MASS (m/z): 325 (M+H)+
Preparation 80
To a solution of N-isopropylcyclohexylamine (3.52 ml) in tetrahydrofuran (10 ml) was added 1M n-butyllithium in hexane (13.8 ml). After being stirred for 20 minutes at this temperature, the solution was treated dropwise with tert-butyl acetate (2.96 ml). And after stirred for 20 minutes, a solution of 2,3-dibromomethyl-1,4-dimethoxybenzene (2.73 g) in tetrahydrofuran (10 ml) was added below xe2x88x9268xc2x0 C. After all had been introduced, the mixture was allowed to warm to xe2x88x9223xc2x0 C. and stirred for 2.5 hours at this temperature. The resulting mixture was added dropwise to 1N hydrochloric acid (10 ml) with stirring under ice-cooling over 30 minutes and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]propionic acid tert-butyl ester (2.69 g).
NMR (CDCl3, xcex4): 1.47 (18H, s), 2.29-2.43 (4H, m), 2.88-2.96 (4H, m), 3.75 (6H, s), 6.66 (2H, s)
Preparation 81
3-[2-(2-tert-butoxycarbonylethyl)-3,6-dimethoxyphenyl]-propionic acid tert-butyl ester (6.33 g) was added dropwise to a refluxed solution of sodium hydride (578 mg) in dry toluene (60 ml) and dry tert-butyl alcohol (0.5 ml), and stirred for 3 hours. After cooling, to the reaction mixture glacial acetic acid was added dropwise followed by addition of ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue were added methanol (50 ml) and 6N hydrochloric acid (15 ml), and this mixture was refluxed for 3 hours, poured into ice and extracted with ethyl acetate. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 1,4-dimethoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one (2.99 g).
MASS (m/z): 221 (M+H)+
Preparation 82
A solution of 1,4-dimethoxy-5,6,8,9-tetrahydrobenzo-cyclohepten-7-one (670 mg) and benzylamine (0.5 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (0.5 g) under nitrogen at 5xc2x0 C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1,4-dimethoxy-5,6,8,9-tetrahydrobenzcyclohepten-7-yl)amine (600 mg).
MASS (m/z): 312 (M+H)+
Preparation 83
Under nitrogen, to fuming nitric acid (60 ml) was added 6,7,8,9-tetrahydrobenzocyclohepten-5-one (20 g) on ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was poured into ice water (200 ml). The precipitates were collected by filtration and dissolved into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g).
(+) APCI-MASS (m/z): 228 (M+Na)+
Preparation 84
A mixture of 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g), iron (14.87 g) and ammonium chloride (2.0 g) in ethanol (200 ml) and water (40 ml) was refluxed for 5 hours, and filtered. The filtrate was evaporated in vacuo to afford 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.86 g).
NMR (CDCl3, xcex4) 1.75-1.90 (4H, m), 2.60-2.90 (6H, m), 6.73-7.07 (3H, m)
Preparation 85
To a solution of 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.53 g) in 10% sulfuric acid (130 ml) was added sodium nitrite (4.9 g) and sodium sulfite (694 mg) under ice-cooling. After being stirred for 20 minutes at this temperature, to the reaction mixture was added toluene (100 ml), stirred at the room temperature for 18 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.08 g).
(+) APCI-MASS (m/z): 177 (M+H)+
Preparation 86
A mixture of 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.02 g), potassium carbonate (8.25 g) and iodomethane (7.4 ml) in N,N-dimethylformamide (70 ml) was stirred at 50-55xc2x0 C. for 7 hours. The resulting mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (5.49 g).
(+) APCI-MASS (m/z): 191 (M+H)+
Preparation 87
A solution of 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-hepten-5-one (6.0 g) and benzylamine (3.4 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water at the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (1.2 g) under nitrogen at 5xc2x0 C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (7.27 g).
(+) APCI-MASS (m/z): 282 (M+H)+
Preparation 88
Methanesulfonyl chloride (1.4 ml) was added dropwise to a solution of acetic acid 3-amino-4-benzylphenyl ester (4.3 g) in pyridine (20 ml) under ice-cooling over 10 minutes, and the mixture was stirred at room temperature for a further 1 hour. Therein was added water (100 ml) and the resulting mixture was stirred at the same temperature for 1 hour. The precipitates were collected by filtration, dissolved into chloroform (100 ml), followed by its dryness over magnesium sulfate and its evaporation in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford acetic acid 4-benzyloxy-3-methanesulfonylaminophenyl ester (1.6 g).
NMR (CDCl3xcex4): 2.27 (3H, s), 2.95 (3H, s), 5.09 (2H, s), 6.80-7.03 (3H, m), 7.25-7.45 (6H, m)
(+) APCI-MASS (m/z): 336 (M+H)+
Preparation 89
A solution of acetic acid 4-benzyloxy-3-methanesulfonylaminophenyl ester (1.6 g) and potassium hydride (2.67 g) in methanol (10 ml) was stirred for 18 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid to pH 5-7 and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford N-(2-benzyloxy-5-hydroxyphenyl)methanesulfonamide (750 mg).
NMR (CDCl3, xcex4): 2.90 (3H, s), 5.04 (2H, s), 6.58 (1H, dd, J=2.9 and 8.8 Hz), 6.80-6.90 (2H, m), 7.09 (1H, d, J=2.9 Hz), 7.30-7.50 (6H, m)
(+) APCI-MASS (m/z): 294 (M+H)+
Preparation 90
Under nitrogen, to a solution of N-(2-benzyloxy-5-hydroxyphenyl)methanesulfonamide (740 mg) and sodium hydride (92.4 mg) in N,N-dimethylformamide (30 ml) was added (2S)-(+)-1-tosyloxy-2,3-epoxypropane (616 mg) at 0xc2x0 C. and the mixture was stirred at the same temperature for 0.5 hour. The mixture was allowed to warm to room temperature and stirred for 2.5 hours at this temperature. The resulting mixture was poured into 10% aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-(4-benzyloxy-3-methanesulfonylamino)phenoxy-2,3-epoxypropane (440 mg).
NMR (CDCl3, xcex4): 2.75 (1H, dd, J=2.7 and 4.9 Hz), 2.84-2.95 (4H, m), 3.30-3.37 (1H, m), 3.90 (1H, dd, J=5.8 and 11.1 Hz), 4.07-4.25 (1H, m), 5.05 (2H, s), 6.63-7.48 (9H, m)
(+) APCI-MASS (m/z): 350 (M+H)+
Preparation 91
To a solution of 2-[8-[(2S)-2-hydroxy-3-phenoxypropylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (3.29 g) and triethylamine (2.55 ml) in tetrahydrofuran (20 ml) was added di-tert-butyl dicarbonate (1.53 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N -tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (3.61 g).
NMR (CDCl3, xcex4): 1.30 (3H, t, J=9.1 Hz), 1.49 (9H, s), 1.50-2.05 (4H, m), 1.60-1.80 (3H, m), 3.20-3.80 (4H, m), 3.90-4.20 (3H, m), 4.27 (2H, q, J=7.1 Hz), 4.57 (1H, s), 6.60-6.70 (2H, s), 6.90-7.05 (4H, m), 7.10-7.38 (2H, m)
Preparation 92
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-h ydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (3.60 g) in ethanol (20 ml) was added 1N sodium hydroxide (7 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was acidified with hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (3.2 g).
NMR (CDCl3, xcex4): 1.49 (9H, s), 1.90-2.05 (4H, m), 2.60-2.80 (3H, m), 3.20-3.75 (4H, m), 3.80-4.30 (3H, m), 4.61 (2H, s), 6.60-6.75 (2H, m), 6.80-7.05 (4H, m), 7.20-7.40 (2H, m)
Preparation 93
Under nitrogen, to a solution of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (300 mg) and 1-[N-phenyl-N-benzyloxycarbonylamino]-2,3-epoxypropane (300 mg) in dichloromethane (5 ml) was added ytterbium(III) trifluoromethanesulfonate (66 mg) at room temperature, and the mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 4:1) to give N-[3-[Nxe2x80x2-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-2-hydroxypropyl[-N-benzyloxycarbonylphenylamine (307 mg).
(+) APCI-MASS (m/z): 565 (M+H)+